研究者詳細 - 永田　安伸

写真a

ナガタ　ヤスノブ

永田　安伸

Nagata Yasunobu

所属

付属病院血液内科講師

外部リンク

研究分野

ライフサイエンス / 血液、腫瘍内科学

論文

Germline DDX41 mutations define a unique subtype of myeloid neoplasms. 国際誌

Hideki Makishima, Ryunosuke Saiki, Yasuhito Nannya, Sophia Claire Korotev, Carmelo Gurnari, June Takeda, Yukihide Momozawa, Steven Best, Pramila Krishnamurthy, Tetsuichi Yoshizato, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Nobuyuki Kakiuchi, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Ayana Kon, Yotaro Ochi, Masahiro Marshall Nakagawa, Rurika Okuda, Takuto Mori, Akinori Yoda, Hidehiro Itonaga, Yasushi Miyazaki, Masashi Sanada, Takayuki Ishikawa, Shigeru Chiba, Hisashi Tsurumi, Senji Kasahara, Carsten Müller-Tidow, Akifumi Takaori-Kondo, Kazuma Ohyashiki, Toru Kiguchi, Fumihiko Matsuda, Joop H Jansen, Chantana Polprasert, Piers Blombery, Yoichiro Kamatani, Satoru Miyano, Luca Malcovati, Torsten Haferlach, Michiaki Kubo, Mario Cazzola, Austin G Kulasekararaj, Lucy A Godley, Jaroslaw P Maciejewski, Seishi Ogawa

Blood 141 ( 5 ) 534 - 549 2022年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）

Germline DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here, enrolling a total of 346 patients with DDX41 pathogenic/likely pathogenic (P/LP) germline variants and/or somatic mutations from 9,082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients, we performed a comprehensive characterization of DDX41-mutated MNs. P/LP DDX41 germline variants explained ~80% of known germline predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n=4,461) compared to a Japanese general population (n=20,238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs. 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years old but rapidly increased to 49% by 90 years of age. DDX41-mutated MDS patients rapidly progressed to AML, which was, however, confined to those having truncating variants. Co-mutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and -WT cases, where none of the co-mutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multi-hit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System (IPSS-R/M). Our findings establish that DDX41-mutated MDS defines a unique subtype of MNs that is distinct from other MNs.

DOI： 10.1182/blood.2022018221

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筋移植片対宿主病発症後に致死的な肺移植片対宿主病を発症したPh陽性急性リンパ性白血病

浅葉惇, 朝山敏夫, 由井俊輔, 丸毛淳史, 尾内大志, 永田安伸, 脇田知志, 山口博樹

臨床血液 63 ( 10 ) 1464 - 1464 2022年10月

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記述言語：日本語出版者・発行元：(一社)日本血液学会-東京事務局

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Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia. 国際誌

June Takeda, Kenichi Yoshida, Masahiro M Nakagawa, Yasuhito Nannya, Akinori Yoda, Ryunosuke Saiki, Yotaro Ochi, Lanying Zhao, Rurika Okuda, Xingxing Qi, Takuto Mori, Ayana Kon, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Ming-Chung Kuo, Cassandra M Kerr, Yasunobu Nagata, Daisuke Morishita, Nobuhiro Hiramoto, Akira Hangaishi, Hideyuki Nakazawa, Ken Ishiyama, Satoru Miyano, Shigeru Chiba, Yasushi Miyazaki, Toshiyuki Kitano, Kensuke Usuki, Nobuo Sezaki, Hisashi Tsurumi, Shuichi Miyawaki, Jaroslaw P Maciejewski, Takayuki Ishikawa, Kazuma Ohyashiki, Arnold Ganser, Michael Heuser, Felicitas Thol, Lee-Yung Shih, Akifumi Takaori-Kondo, Hideki Makishima, Seishi Ogawa

Blood cancer discovery 3 ( 5 ) 410 - 427 2022年9月

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記述言語：英語掲載種別：研究論文（学術雑誌）

UNLABELLED: Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. SIGNIFICANCE: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369.

DOI： 10.1158/2643-3230.BCD-21-0192

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骨髄異形成症候群におけるSRSF2変異とSTAG2変異と協調的関係(Cooperative effects of SRSF2 and STAG2 mutations on development of myelodysplastic syndrome and its related disorders)

森拓人, 越智陽太郎, 昆彩奈, 吉里哲一, 古関明彦, 依田成玄, 中川正宏, 竹田淳恵, 永田安伸, 吉田健一, 眞田昌, 牧島秀樹, 高折晃史, 熱田由子, 南谷泰仁, 小川誠司

日本癌学会総会記事 81回 IS11 - 6 2022年9月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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Safety and efficacy of high-dose cytarabine MEAM therapy and other treatments for auto-peripheral blood stem cell transplantation: A retrospective comparative study. 国際誌

Shunsuke Yui, Satoshi Wakita, Yasunobu Nagata, Yasuko Kuribayashi, Toshio Asayama, Yusuke Fujiwara, Masahiro Sakaguchi, Satoshi Yamanaka, Atsushi Marumo, Ikuko Omori, Ryosuke Kinoshita, Daishi Onai, Mika Sunakawa, Yuta Kaito, Kazuki Inai, Taichiro Tokura, Atsushi Takeyoshi, Shunichi Yasuda, Shunsuke Honma, Kazutaka Nakayama, Tsuneaki Hirakawa, Kunihito Arai, Tomoaki Kitano, Muneo Okamoto, Koiti Inokuchi, Hiroki Yamaguchi

Asia-Pacific journal of clinical oncology 19 ( 1 ) 136 - 148 2022年5月

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記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400 mg/m2 for 4 days, but we decided to increase the dosage of Ara-C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high-dose Ara-C MEAM therapy. METHODS: The high-dose Ara-C MEAM protocol consisted of MCNU 300 mg/m2 on day -7, ETP 200 mg/m2 on days -6, -5, -4, -3 and Ara-C 2 g/m2 on day -4 -3, and MEL 140 mg/m2 on day -2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020. RESULTS: All patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively. CONCLUSION: The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

DOI： 10.1111/ajco.13780

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好酸球増多を伴う骨髄異形成症候群に劇症型好酸球性心筋症を合併した1剖検例

竹吉敦志, 脇田知志, 本間俊佑, 保田駿一, 土蔵太一郎, 稲井一貴, 丸毛淳史, 山中聡, 阪口正洋, 永田安伸, 由井俊輔, 岡本宗雄, 山口博樹

臨床血液 63 ( 5 ) 494 - 494 2022年5月

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記述言語：日本語出版者・発行元：(一社)日本血液学会-東京事務局

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予後不良因子を複数伴った化学療法抵抗性のCD19陽性AMLに対して臍帯血移植が奏効した1例

山口玲, 阪口正洋, 稲井一貴, 土蔵太一朗, 竹吉敦志, 保田駿一, 本間俊佑, 尾内大志, 砂川実香, 丸毛淳史, 山中聡, 朝山敏夫, 永田安伸, 由井俊輔, 脇田知志, 岡本宗雄, 山口博樹, 猪口孝一

臨床血液 62 ( 10 ) 1522 - 1522 2021年10月

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記述言語：日本語出版者・発行元：(一社)日本血液学会-東京事務局

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ETNK1 mutations defines a subclass of der(1;7)(q10;p10) in myelodysplastic syndromes(和訳中)

奥田瑠璃花, 南谷泰人, 越智陽太郎, 蝶名林和久, 牧島秀樹, 吉里哲一, 永田安伸, 竹田淳恵, 吉田健一, 眞田昌, 昆彩奈, 白石雄一, 宮野悟, 熱田由子, 笠原千嗣, 半田寛, 千葉滋, 大屋敷一馬, 吉田善紀, 小川誠司

日本血液学会学術集会 83回 OS1 - 4 2021年9月

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記述言語：英語出版者・発行元：(一社)日本血液学会

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ETNK1変異の有無を特徴とするder(1;7)(q10;p10)を伴う骨髄異形成症候群

奥田瑠璃花, 南谷泰仁, 越智陽太郎, 蝶名林和久, 牧島秀樹, 永田安伸, 真田昌, 白石友一, 宮野悟, 熱田由子, 笠原千嗣, 半田寛, 千葉滋, 大屋敷一馬, 小川誠司

日本癌学会総会記事 80回 [E7 - 2] 2021年9月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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赤白血病におけるゲノム解析と治療標的の検討

竹田淳恵, 吉田健一, 依田成玄, 南谷泰仁, 越智陽太郎, 中川正宏, 佐伯龍之介, 白石友一, 永田安伸, 高折晃史, 千葉滋, 片岡圭亮, 宮野悟, 牧島秀樹, 小川誠司

日本癌学会総会記事 80回 [J7 - 1] 2021年9月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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当院における移植後肺合併症の検討(Clinical characteristics of noninfectious lung complication in allogenic stem cell transplantation)

朝山敏夫, 由井俊輔, 脇田知志, 永田安伸, 栗林泰子, 藤原裕介, 阪口正洋, 山中聡, 丸毛淳史, 大森郁子, 木下量介, 砂川実香, 海渡裕太, 尾内大志, 稲井一貴, 土蔵太一朗, 本間俊祐, 竹吉敦志, 保田駿一, 岡本宗雄, 猪口孝一, 山口博樹

日本血液学会学術集会 83回 PS - 3 2021年9月

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記述言語：英語出版者・発行元：(一社)日本血液学会

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全自動遺伝子解析装置i-densy IS-5320を用いた造血器腫瘍における転座型遺伝子異常検出の有用性の検討(Examination of the usefulness of translocation-type gene abnormality detection using i-densy IS-5320)

由井俊輔, 岡本宗雄, 脇田知志, 永田安伸, 栗林泰子, 朝山敏夫, 藤原裕介, 阪口正洋, 山中聡, 丸毛淳史, 大森郁子, 木下量介, 尾内大志, 砂川実香, 海渡裕太, 稲井一貴, 土蔵太一朗, 竹吉敦志, 保田駿一, 本間俊佑, 荒井邦仁, 北野智章, 宮田美保, 土岐典子, 諫田淳也, 平井光春, 木寺一喜, 猪口孝一, 山口博樹

日本血液学会学術集会 83回 PS - 2 2021年9月

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記述言語：英語出版者・発行元：(一社)日本血液学会

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Machine learning demonstrates that somatic mutations imprint invariant morphologic features in myelodysplastic syndromes. 査読国際誌

Yasunobu Nagata, Ran Zhao, Hassan Awada, Cassandra M Kerr, Inom Mirzaev, Sunisa Kongkiatkamon, Aziz Nazha, Hideki Makishima, Tomas Radivoyevitch, Jacob G Scott, Mikkael A Sekeres, Brian P Hobbs, Jaroslaw P Maciejewski

Blood 136 ( 20 ) 2249 - 2262 2020年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）

Morphologic interpretation is the standard in diagnosing myelodysplastic syndrome (MDS), but it has limitations, such as varying reliability in pathologic evaluation and lack of integration with genetic data. Somatic events shape morphologic features, but the complexity of morphologic and genetic changes makes clear associations challenging. This article interrogates novel clinical subtypes of MDS using a machine-learning technique devised to identify patterns of cooccurrence among morphologic features and genomic events. We sequenced 1079 MDS patients and analyzed bone marrow morphologic alterations and other clinical features. A total of 1929 somatic mutations were identified. Five distinct morphologic profiles with unique clinical characteristics were defined. Seventy-seven percent of higher-risk patients clustered in profile 1. All lower-risk (LR) patients clustered into the remaining 4 profiles: profile 2 was characterized by pancytopenia, profile 3 by monocytosis, profile 4 by elevated megakaryocytes, and profile 5 by erythroid dysplasia. These profiles could also separate patients with different prognoses. LR MDS patients were classified into 8 genetic signatures (eg, signature A had TET2 mutations, signature B had both TET2 and SRSF2 mutations, and signature G had SF3B1 mutations), demonstrating association with specific morphologic profiles. Six morphologic profiles/genetic signature associations were confirmed in a separate analysis of an independent cohort. Our study demonstrates that nonrandom or even pathognomonic relationships between morphology and genotype to define clinical features can be identified. This is the first comprehensive implementation of machine-learning algorithms to elucidate potential intrinsic interdependencies among genetic lesions, morphologies, and clinical prognostic in attributes of MDS.

DOI： 10.1182/blood.2020005488

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Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. 査読国際誌

Yosaku Watatani, Yasuharu Sato, Hiroaki Miyoshi, Kana Sakamoto, Kenji Nishida, Yuka Gion, Yasunobu Nagata, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Lanying Zhao, Yotaro Ochi, Yasuhide Takeuchi, June Takeda, Hiroo Ueno, Yasunori Kogure, Yusuke Shiozawa, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Masahiro M Nakagawa, Yasuhito Nanya, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Mamiko Sakata-Yanagimoto, Shigeru Chiba, Ryota Matsuoka, Masayuki Noguchi, Nobuhiro Hiramoto, Takayuki Ishikawa, Junichi Kitagawa, Nobuhiko Nakamura, Hisashi Tsurumi, Tatsuhiko Miyazaki, Yusuke Kito, Satoru Miyano, Kazuya Shimoda, Kengo Takeuchi, Koichi Ohshima, Tadashi Yoshino, Seishi Ogawa, Keisuke Kataoka

Leukemia 33 ( 12 ) 2867 - 2883 2019年12月

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記述言語：英語掲載種別：研究論文（学術雑誌）

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

DOI： 10.1038/s41375-019-0473-1

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Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes. 査読国際誌

Nagata Y, Makishima H, Kerr CM, Przychodzen BP, Aly M, Goyal A, Awada H, Asad MF, Kuzmanovic T, Suzuki H, Yoshizato T, Yoshida K, Chiba K, Tanaka H, Shiraishi Y, Miyano S, Mukherjee S, LaFramboise T, Nazha A, Sekeres MA, Radivoyevitch T, Haferlach T, Ogawa S, Maciejewski JP

Nature communications 10 ( 1 ) 5386 - 5386 2019年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038/s41467-019-13001-y

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Large granular lymphocytic leukemia coexists with myeloid clones and myelodysplastic syndrome. 査読

Durrani J, Awada H, Kishtagari A, Visconte V, Kerr C, Adema V, Nagata Y, Kuzmanovic T, Hong S, Patel B, Nazha A, Lichtin A, Mukherjee S, Saunthararajah Y, Carraway H, Sekeres M, Maciejewski JP

Leukemia 2019年10月

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DOI： 10.1038/s41375-019-0601-y

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The functional mechanisms of mutations in myelodysplastic syndrome. 査読

Nagata Y, Maciejewski JP

Leukemia 2019年10月

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DOI： 10.1038/s41375-019-0617-3

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骨髄異形成症候群におけるder(1;7)の臨床的、遺伝学的特徴(Distinct ethnic, clinical, and genetic characteristics of der(1;7) in myelodysplastic syndromes)

奥田瑠璃花, 牧島秀樹, 吉里哲一, 南谷泰仁, 永田安伸, 越智陽太郎, 竹田淳恵, 吉田健一, 眞田昌, 白石友一, 宮野悟, 熱田由子, 小川誠司

日本癌学会総会記事 78回 P - 2376 2019年9月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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Genomics of therapy-related myeloid neoplasms. 査読

Kuzmanovic T, Patel BJ, Sanikommu SR, Nagata Y, Awada H, Kerr CM, Przychodzen BP, Jha BK, Hiwase D, Singhal D, Advani AS, Nazha A, Gerds AT, Carraway HE, Sekeres MA, Mukherjee S, Maciejewski JP, Radivoyevitch T

Haematologica 2019年8月

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DOI： 10.3324/haematol.2019.219352

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Leukemia evolving from paroxysmal nocturnal hemoglobinuria. 査読

Awada H, Rahman S, Durrani J, Asad MF, Kerr CM, Adema V, Kishtagari A, Graham A, Snider CA, Kongkiatkamon S, Nagata Y, Patel BJ, Carraway HE, Sekeres MA, Maciejewski JP, Visconte V

Leukemia 2019年8月

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DOI： 10.1038/s41375-019-0555-0

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Distinct clinical and biological implications of CUX1 in myeloid neoplasms. 査読国際誌

Aly M, Ramdzan ZM, Nagata Y, Balasubramanian SK, Hosono N, Makishima H, Visconte V, Kuzmanovic T, Adema V, Nazha A, Przychodzen BP, Kerr CM, Sekeres MA, Abazeed ME, Nepveu A, Maciejewski JP

Blood advances 3 ( 14 ) 2164 - 2178 2019年7月

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記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1182/bloodadvances.2018028423

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TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. 査読国際誌

Haase D, Stevenson KE, Neuberg D, Maciejewski JP, Nazha A, Sekeres MA, Ebert BL, Garcia-Manero G, Haferlach C, Haferlach T, Kern W, Ogawa S, Nagata Y, Yoshida K, Graubert TA, Walter MJ, List AF, Komrokji RS, Padron E, Sallman D, Papaemmanuil E, Campbell PJ, Savona MR, Seegmiller A, Adès L, Fenaux P, Shih LY, Bowen D, Groves MJ, Tauro S, Fontenay M, Kosmider O, Bar-Natan M, Steensma D, Stone R, Heuser M, Thol F, Cazzola M, Malcovati L, Karsan A, Ganster C, Hellström-Lindberg E, Boultwood J, Pellagatti A, Santini V, Quek L, Vyas P, Tüchler H, Greenberg PL, Bejar R, International Working, Group for, MDS Molecular, Prognostic Committee

Leukemia 33 ( 7 ) 1747 - 1758 2019年7月

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記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1038/s41375-018-0351-2

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Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure. 査読

Shen W, Kerr CM, Przychozen B, Mahfouz RZ, LaFramboise T, Nagata Y, Hanna R, Radivoyevitch T, Nazha A, Sekeres MA, Maciejewski JP

British journal of haematology 185 ( 5 ) 935 - 939 2019年6月

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DOI： 10.1111/bjh.15862

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Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. 査読

Watatani Y, Sato Y, Miyoshi H, Sakamoto K, Nishida K, Gion Y, Nagata Y, Shiraishi Y, Chiba K, Tanaka H, Zhao L, Ochi Y, Takeuchi Y, Takeda J, Ueno H, Kogure Y, Shiozawa Y, Kakiuchi N, Yoshizato T, Nakagawa MM, Nanya Y, Yoshida K, Makishima H, Sanada M, Sakata-Yanagimoto M, Chiba S, Matsuoka R, Noguchi M, Hiramoto N, Ishikawa T, Kitagawa J, Nakamura N, Tsurumi H, Miyazaki T, Kito Y, Miyano S, Shimoda K, Takeuchi K, Ohshima K, Yoshino T, Ogawa S, Kataoka K

Leukemia. 59 113 - 113 2019年5月

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記述言語：英語掲載種別：研究論文（学術雑誌）

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Subclonal STAT3 mutations solidify clonal dominance. 査読

Kerr CM, Clemente MJ, Chomczynski PW, Przychodzen B, Nagata Y, Adema V, Visconte V, Lichtin AE, Mustjoki S, Radivoyevitch T, Sekeres MA, Maciejewski JP

Blood advances 3 ( 6 ) 917 - 921 2019年3月

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DOI： 10.1182/bloodadvances.2018027862

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Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia. 査読

Awada H, Nagata Y, Goyal A, Asad MF, Patel B, Hirsch CM, Kuzmanovic T, Guan Y, Przychodzen BP, Aly M, Adema V, Shen W, Williams L, Nazha A, Abazeed ME, Sekeres MA, Radivoyevitch T, Haferlach T, Jha BK, Visconte V, Maciejewski JP

Blood advances 3 ( 3 ) 339 - 349 2019年2月

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DOI： 10.1182/bloodadvances.2018024216

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Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study. 査読

Kawashima N, Akashi A, Nagata Y, Kihara R, Ishikawa Y, Asou N, Ohtake S, Miyawaki S, Sakura T, Ozawa Y, Usui N, Kanamori H, Ito Y, Imai K, Suehiro Y, Kitamura K, Sakaida E, Takeshita A, Suzushima H, Naoe T, Matsumura I, Miyazaki Y, Ogawa S, Kiyoi H, Japan Adult Leukemia Study Group (JALSG

Annals of hematology 98 ( 1 ) 83 - 91 2019年1月

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DOI： 10.1007/s00277-018-3492-5

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Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. 査読国際誌

Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, Shima H, Aly M, Pastor V, Kuzmanovic T, Radivoyevitch T, Adema V, Awada H, Yoshida K, Li S, Sole F, Hanna R, Jha BK, LaFramboise T, Ogawa S, Sekeres MA, Wlodarski MW, Cammenga J, Maciejewski JP

Blood 132 ( 21 ) 2309 - 2313 2018年11月

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記述言語：英語

DOI： 10.1182/blood-2017-05-787390

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Clonal PIGA mosaicism and dynamics in paroxysmal nocturnal hemoglobinuria. 査読

Clemente MJ, Przychodzen B, Hirsch CM, Nagata Y, Bat T, Wlodarski MW, Radivoyevitch T, Makishima H, Maciejewski JP

Leukemia 32 ( 11 ) 2507 - 2511 2018年11月

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DOI： 10.1038/s41375-018-0138-5

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Prognostic Analysis According to the 2017 ELN Risk Stratification by Genetics in Adult Acute Myeloid Leukemia Patients Treated in The Japan Adult Leukemia Study Group (JALSG) AML201 study 査読

Harada Yasuhiko, Nagata Yasunobu, Kihara Rika, Ishikawa Yuichi, Asou Norio, Ohtake Shigeki, Miyawaki Shuichi, Sakura Toru, Ozawa Yukiyasu, Usui Noriko, Kanamori Heiwa, Ito Yoshikazu, Imai Kiyotoshi, Suehiro Youko, Kobayashi Shinichi, Kitamura Kunio, Sakaida Emiko, Onizuka Makoto, Takeshita Akihiro, Ishida Fumihiro, Suzushima Hitoshi, Ishizawa Kenichi, Naoe Tomoki, Matsumura Itaru, Miyazaki Yasushi, Ogawa Seishi, Kiyoi Hitoshi

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 18 S196 2018年9月

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DOI： 10.1016/j.clml.2018.07.040

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骨髄異形成症候群患者320例におけるDNAメチル化と遺伝子プロファイル(DNA methylation and genetic profiles in 320 patients with myelodysplastic syndromes) 査読

森本俊, 牧島秀樹, 永田安伸, Baer Constance, Nadarajah Niroshan, Alpermann Tamara, 永江玄太, 南谷泰仁, 宮崎泰司, 吉田健一, 吉里哲一, 中川正宏, 稲垣良作, 竹田淳恵, 藤井陽一, 竹内康英, 白石友一, 千葉健一, 田中洋子, 眞田昌, 宮野悟, Haferlach Claudia, Kern Wolfgang, 油谷浩幸, Haferlach Torsten, 小川誠司

臨床血液 59 ( 9 ) 1519 - 1519 2018年9月

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記述言語：英語出版者・発行元：(一社)日本血液学会-東京事務局

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ゲノム解析から見た赤白血病(Genomic characteristics of acute erythroid leukemia)

竹田淳恵, Shih Lee-Yung, 千葉健一, 白石友一, 塩澤裕介, 牧島秀樹, 吉里哲一, 永田安伸, 半下石明, 石山謙, 鶴見寿, 宮崎泰司, 平本展大, 石川隆之, 高折晃史, 片岡圭亮, 眞田昌, 田中洋子, 臼杵憲祐, 宮脇修一, 宮野悟, Ganser Arnold, Heuser Michael, Thol Felicitas, 昆彩奈, 南谷泰仁, 吉田健一, 小川誠司

臨床血液 59 ( 9 ) 1521 - 1521 2018年9月

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記述言語：英語出版者・発行元：(一社)日本血液学会-東京事務局

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Consequences of mutant TET2 on clonality and subclonal hierarchy. 査読

Hirsch CM, Nazha A, Kneen K, Abazeed ME, Meggendorfer M, Przychodzen BP, Nadarajah N, Adema V, Nagata Y, Goyal A, Awada H, Asad MF, Visconte V, Guan Y, Sekeres MA, Olinski R, Jha BK, LaFramboise T, Radivoyevitch T, Haferlach T, Maciejewski JP

Leukemia 32 ( 8 ) 1751 - 1761 2018年8月

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DOI： 10.1038/s41375-018-0150-9

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Idh1/2 mutations sensitize acute myeloid leukemia to parp inhibition and this is reversed by idh1/2-mutant inhibitors 査読

Remco J. Molenaar, Tomas Radivoyevitch, Yasunobu Nagata, Mohammed Khurshed, Bartolomiej Przychodzen, Hideki Makishima, Mingjiang Xu, Fonnet E. Bleeker, Johanna W. Wilmink, Hetty E. Carraway, Sudipto Mukherjee, Mikkael A. Sekeres, Cornelis J.F. van Noorden, Jaroslaw P. Maciejewski

Clinical Cancer Research 24 ( 7 ) 1705 - 1715 2018年4月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Association for Cancer Research Inc.

Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known. Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT, and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors. Results: IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells. Conclusions: IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML.

DOI： 10.1158/1078-0432.CCR-17-2796

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Prognostic analysis according to the 2017 ELN risk stratification by genetics in adult acute myeloid leukemia patients treated in the Japan Adult Leukemia Study Group (JALSG) AML201 study 査読

Yasuhiko Harada, for the Japan Adult Leukemia Study Group JALSG, Yasunobu Nagata, Rika Kihara, Yuichi Ishikawa, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Shinichi Kobayashi, Kunio Kitamura, Emiko Sakaida, Makoto Onizuka, Akihiro Takeshita, Fumihiro Ishida, Hitoshi Suzushima, Kenichi Ishizawa, Tomoki Naoe, Itaru Matsumura, Yasushi Miyazaki, Seishi Ogawa, Hitoshi Kiyoi

Leukemia Research 66 20 - 27 2018年3月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier Ltd

Many genetic alterations that are associated with the prognosis of acute myeloid leukemia (AML) have been identified, and several risk stratification systems based on the genetic status have been recommended. The European LeukemiaNet (ELN) first proposed the risk stratification system for AML in 2010 (ELN-2010), and recently published the revised system (ELN-2017). We validated the long-term prognosis and clinical characteristics of each ELN-2017 risk category in Japanese adult AML patients who were treated in the Japan Adult Leukemia Study Group (JALSG) AML-201 study. We demonstrated that the 3-risk category system of the ELN-2017 successfully discriminated the overall survival and complete remission rates in our cohort in comparison with the 4-risk category of the ELN-2010. However, there were still genetic categories in which stratification of patients into favorable or intermediate risk categories was controversial
the low allelic ratio of FLT3-ITD was not necessarily associated with a better prognosis in patients with FLT3-ITD, and cytogenetic abnormalities may affect the prognosis in patients with favorable genetic lesions such as NPM1 and CEBPA mutations. As many molecular targeting agents, such as FLT3 inhibitors, have been developed, we must continue to modify the genetic risk stratification system to match the progression of therapeutic strategies.

DOI： 10.1016/j.leukres.2018.01.008

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Distinct gene alterations with a high percentage of myeloperoxidase-positive leukemic blasts in de novo acute myeloid leukemia. 査読国際誌

Rena Kamijo, Hidehiro Itonaga, Rika Kihara, Yasunobu Nagata, Tomoko Hata, Norio Asou, Shigeki Ohtake, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Tomoki Naoe, Hitoshi Kiyoi, Yasushi Miyazaki

Leukemia research 65 34 - 41 2018年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）

The myeloperoxidase (MPO)-positivity of blasts in bone marrow smears is an important marker for not only the diagnosis, but also the prognosis of acute myeloid leukemia (AML). To investigate the relationship between genetic alterations and MPO-positivity, we performed targeted sequencing for 51 genes and 10 chimeric gene transcripts in 164 newly diagnosed de novo AML patients; 107 and 57 patients were classified as AML with >50% MPO-positive blasts (MPO-high group) and ≤50% MPO-positive blasts, (MPO-low group), respectively. The univariate analysis revealed that RUNX1-RUNX1T1 (P < 0.001), the KIT mutation (P < 0.001), and CEBPA double mutation (P = 0.001) were more likely to be found in the MPO-high group, while the DNMT3A mutation (P = 0.001), FLT3 tyrosine kinase domain mutation (P = 0.004), and TP53 mutation (P = 0.020) were more likely to be present in the MPO-low group. Mutations in genes related to DNA hypermethylation signatures (IDH1, IDH2, TET2, and WT1 genes) were more frequent in the MPO-high group (P = 0.001) when patients with fusion genes of core-binding factors were excluded from the analysis. Our results suggest that MPO-positivity of blasts was related with the distinct gene mutation patterns among de novo AML patients.

DOI： 10.1016/j.leukres.2017.12.006

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Prognostic value of genetic mutations in adolescent and young adults with acute myeloid leukemia. 査読

Yachiyo Kuwatsuka, Daisuke Tomizawa, Rika Kihara, Yasunobu Nagata, Norio Shiba, Yuka Iijima-Yamashita, Akira Shimada, Takao Deguchi, Hayato Miyachi, Akio Tawa, Takashi Taga, Akitoshi Kinoshita, Hideki Nakayama, Nobutaka Kiyokawa, Akiko Moriya Saito, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Yasushi Miyazaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Shinichi Kobayashi, Kunio Kitamura, Emiko Sakaida, Seishi Ogawa, Tomoki Naoe, Yasuhide Hayashi, Keizo Horibe, Atsushi Manabe, Shuki Mizutani, Souichi Adachi, Hitoshi Kiyoi

International journal of hematology 107 ( 2 ) 201 - 210 2018年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）

Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years. FLT3-ITD (HR 2.10; 95% CI 1.07-4.12; p = 0.031) and NPM1 (HR 0.24; 95% CI 0.06-1.00; p = 0.050) mutations were associated with risk of overall mortality in multivariate analysis. OS was significantly different according to FLT3-ITD and NPM1 mutation status (p = 0.03). Survival was 100% with NPM1 mutations in the absence of FLT3-ITD and 35% (95% CI 14-57%) with FLT3-ITD in the absence of NPM1 mutations. The OS of AYAs, children (n = 413) and older adults (n = 124) of the AML-05 and AML201 participants were significantly different (p < 0.0001). This is the first report to combine clinical and genetic data of AYA AML from the major Japanese pediatric and adult study groups.

DOI： 10.1007/s12185-017-2340-z

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Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma. 査読国際誌

Keisuke Kataoka, Masako Iwanaga, Jun-Ichirou Yasunaga, Yasunobu Nagata, Akira Kitanaka, Takuro Kameda, Makoto Yoshimitsu, Yuichi Shiraishi, Aiko Sato-Otsubo, Masashi Sanada, Kenichi Chiba, Hiroko Tanaka, Yotaro Ochi, Kosuke Aoki, Hiromichi Suzuki, Yusuke Shiozawa, Tetsuichi Yoshizato, Yusuke Sato, Kenichi Yoshida, Kisato Nosaka, Masakatsu Hishizawa, Hidehiro Itonaga, Yoshitaka Imaizumi, Wataru Munakata, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Tsuyoshi Nakamaki, Ken Ishiyama, Shuichi Miyawaki, Ryohei Ishii, Osamu Nureki, Kensei Tobinai, Yasushi Miyazaki, Akifumi Takaori-Kondo, Tatsuhiro Shibata, Satoru Miyano, Kenji Ishitsuka, Atae Utsunomiya, Kazuya Shimoda, Masao Matsuoka, Toshiki Watanabe, Seishi Ogawa

Blood 131 ( 2 ) 215 - 225 2018年1月

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記述言語：英語掲載種別：研究論文（学術雑誌）

Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

DOI： 10.1182/blood-2017-01-761874

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Prognostic relevance of genetic alterations in diffuse lower-grade gliomas 査読

Kosuke Aoki, Hideo Nakamura, Hiromichi Suzuki, Keitaro Matsuo, Keisuke Kataoka, Teppei Shimamura, Kazuya Motomura, Fumiharu Ohka, Satoshi Shiina, Takashi Yamamoto, Yasunobu Nagata, Tetsuichi Yoshizato, Masahiro Mizoguchi, Tatsuya Abe, Yasutomo Momii, Yoshihiro Muragaki, Reiko Watanabe, Ichiro Ito, Masashi Sanada, Hironori Yajima, Naoya Morita, Ichiro Takeuchi, Satoru Miyano, Toshihiko Wakabayashi, Seishi Ogawa, Atsushi Natsume

Neuro-Oncology 20 ( 1 ) 66 - 77 2018年1月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press

Background Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown. Methods Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA). Results In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P &lt
0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA. Conclusions Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.

DOI： 10.1093/neuonc/nox132

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Origins of myelodysplastic syndromes after aplastic anemia 査読

Eiju Negoro, Yasunobu Nagata, Michael J. Clemente, Naoko Hosono, Wenyi Shen, Aziz Nazha, Tetsuichi Yoshizato, Cassandra Hirsch, Bartlomiej Przychodzen, Reda Z. Mahfouz, Teodora Kuzmanovic, Mikkael A. Sekeres, Hideki Makishima, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 130 ( 17 ) 1953 - 1957 2017年10月

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記述言語：英語出版者・発行元：AMER SOC HEMATOLOGY

DOI： 10.1182/blood-2017-02-767731

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Mutational profiling of MLL-PTD acute myeloid leukemia 査読

Ding Lingwen, Sun Qiaoyang, Tan Kar-Tong, Chien Wenwen, Mayakonda Anand, Lin Dechen, Loh Xinyi, Xiao Jinfen, Meggendorfer Manja, Alpermann Tamara, Garg Manoj, Lim Su-Lin, Madan Vikas, Hattori Norimichi, Nagata Yasunobu, Miyano Satoru, Juh Allen Yeoh Eng, Hou Hsin-An, Jiang Yan-Yi, Jiang Yan-Yi, Takao Sumiko, Liu Li-Zhen, Tan Siew-Zhuan, Tan Siew-Zhuan, Lill Michael, Hayashi Mutsumi, Kinoshita Akitoshi, Kantarjian Hagop M, Kornblau Steven M, Ogawa Seishi, Haferlach Torsten, Yang Henry, Koeffler H. Phillip

CANCER RESEARCH 77 2017年7月

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記述言語：英語

DOI： 10.1158/1538-7445.AM2017-2450

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Molecular features of early onset adult myelodysplastic syndrome 査読

Cassandra M. Hirsch, Bartlomiej P. Przychodzen, Tomas Radivoyevitch, Bhumika Patel, Swapna Thota, Michael J. Clemente, Yasunobu Nagata, Thomas LaFramboise, Hetty E. Carraway, Aziz Nazha, Mikkael A. Sekeres, Hideki Makishima, Jaroslaw P. Maciejewski

HAEMATOLOGICA 102 ( 6 ) 1028 - 1034 2017年6月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：FERRATA STORTI FOUNDATION

Myelodysplastic syndromes are typically diseases of older adults. Patients in whom the onset is early may have distinct molecular and clinical features or reflect a demographic continuum. The identification of differences between "early onset" patients and those diagnosed at a traditional age has the potential to advance understanding of the pathogenesis of myelodysplasia and may lead to formation of distinct morphological subcategories. We studied a cohort of 634 patients with various subcategories of myelodysplastic syndrome and secondary acute myeloid leukemia, stratifying them based on age at presentation and clinical parameters. We then characterized molecular abnormalities detected by next-generation deep sequencing of 60 genes that are commonly mutated in myeloid malignancies. The number of mutations increased linearly with age and on average, patients > 50 years of age had more mutations. TET2, SRSF2, and DNMT3A were more commonly mutated in patients > 50 years old compared to patients <= 50 years old. In general, patients > 50 years of age also had more mutations in spliceosomal, epigenetic modifier, and RAS gene families. Although there are age-related differences in molecular features among patients with myelodysplasia, most notably in the incidence of SRSF2 mutations, our results suggest that patients <= 50 years old belong to a disease continuum with a distinct pattern of early onset ancestral events.

DOI： 10.3324/haematol.2016.159772

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Correction: Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution. 査読国際誌

Ryutaro Uchi, Yusuke Takahashi, Atsushi Niida, Teppei Shimamura, Hidenari Hirata, Keishi Sugimachi, Genta Sawada, Takeshi Iwaya, Junji Kurashige, Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi, Kenichi Chiba, Yuichi Shiraishi, Genta Nagae, Kenichi Yoshida, Yasunobu Nagata, Hiroshi Haeno, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Hisae Iinuma, Shin Sasaki, Satoshi Nagayama, Kazutaka Yamada, Shinichi Yachida, Mamoru Kato, Tatsuhiro Shibata, Eiji Oki, Hiroshi Saeki, Ken Shirabe, Yoshinao Oda, Yoshihiko Maehara, Shizuo Komune, Masaki Mori, Yutaka Suzuki, Ken Yamamoto, Hiroyuki Aburatani, Seishi Ogawa, Satoru Miyano, Koshi Mimori

PLoS genetics 13 ( 5 ) e1006798 2017年5月

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記述言語：英語

[This corrects the article DOI: 10.1371/journal.pgen.1005778.].

DOI： 10.1371/journal.pgen.1006798

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Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation 査読

Tetsuichi Yoshizato, Yasuhito Nannya, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Hiromichi Suzuki, Yasunobu Nagata, Yusuke Sato, Nobuyuki Kakiuchi, Keitaro Matsuo, Makoto Onizuka, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Hiroo Ueno, Masahiro M. Nakagawa, Bartlomiej Przychodzen, Claudia Haferlach, Wolfgang Kern, Kosuke Aoki, Hidehiro Itonaga, Yoshinobu Kanda, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Torsten Haferlach, Yasushi Miyazaki, Keizo Horibe, Masashi Sanada, Satoru Miyano, Hideki Makishima, Seishi Ogawa

BLOOD 129 ( 17 ) 2347 - 2358 2017年4月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC HEMATOLOGY

Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.

DOI： 10.1182/blood-2016-12-754796

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Dynamics of clonal evolution in myelodysplastic syndromes 査読

Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, Mikkael A. Sekeres, Tomas Radivoyevitch, Hiromichi Suzuki, Bartlomiej Przychodzen, Yasunobu Nagata, Manja Meggendorfer, Masashi Sanada, Yusuke Okuno, Cassandra Hirsch, Teodora Kuzmanovic, Yusuke Sato, Aiko Sato-Otsubo, Thomas LaFramboise, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Claudia Haferlach, Wolfgang Kern, Hiroko Tanaka, Yusuke Shiozawa, Ines Gomez-Segui, Holleh D. Husseinzadeh, Swapna Thota, Kathryn M. Guinta, Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Torsten Haferlach, Seishi Ogawa, Jaroslaw P. Maciejewski

NATURE GENETICS 49 ( 2 ) 204 - 212 2017年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using wholeexome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones. Enriched in secondary acute myeloid leukemia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (type 1) tended to be newly acquired, and were associated with faster sAML progression and a shorter overall survival time. Significantly enriched in high-risk MDS (in comparison to low-risk MDS), TP53, GATA2, KRAS, RUNX1, STAG2, ASXL1, ZRSR2 and TET2 mutations (type 2) had a weaker impact on sAML progression and overall survival than type-1 mutations. The distinct roles of type-1 and type-2 mutations suggest their potential utility in disease monitoring.

DOI： 10.1038/ng.3742

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Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD) 査読

Q-Y Sun, L-W Ding, K-T Tan, W. Chien, A. Mayakonda, D-C Lin, X-Y Loh, J-F Xiao, M. Meggendorfer, T. Alpermann, M. Garg, S-L Lim, V. Madan, N. Hattori, Y. Nagata, S. Miyano, A. E. J. Yeoh, H-A Hou, Y-Y Jiang, S. Takao, L-Z Liu, S-Z Tan, M. Lill, M. Hayashi, A. Kinoshita, H. M. Kantarjian, S. M. Kornblau, S. Ogawa, T. Haferlach, H. Yang, H. P. Koeffler

LEUKEMIA 31 ( 1 ) 1 - 10 2017年1月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.

DOI： 10.1038/leu.2016.160

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Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia 査読

Ling-Wen Ding, Qiao-Yang Sun, Kar-Tong Tan, Wenwen Chien, Anand Mayakonda Thippeswamy, Allen Eng Juh Yeoh, Norihiko Kawamata, Yasunobu Nagata, Jin-Fen Xiao, Xin-Yi Loh, De-Chen Lin, Manoj Garg, Yan-Yi Jiang, Liang Xu, Su-Lin Lim, Li-Zhen Liu, Vikas Madan, Masashi Sanada, Lucia Torres Fernandez, Hema Preethi, Michael Lill, Hagop M. Kantarjian, Steven M. Kornblau, Satoru Miyano, Der-Cherng Liang, Seishi Ogawa, Lee-Yung Shih, Henry Yang, H. Phillip Koeffler

CANCER RESEARCH 77 ( 2 ) 390 - 400 2017年1月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC CANCER RESEARCH

Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) ismainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. (C) 2016 AACR.

DOI： 10.1158/0008-5472.CAN-16-1303

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A novel prognostic model incorporating genetic profiling for myelodysplastic syndromes. 査読

Nagata Y, Ogawa S

[Rinsho ketsueki] The Japanese journal of clinical hematology 58 ( 7 ) 776 - 786 2017年

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DOI： 10.11406/rinketsu.58.776

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Somatic mosaicism in chronic myeloid leukemia in remission 査読

Kinuko Mitani, Yasunobu Nagata, Ko Sasaki, Kenichi Yoshida, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Satoru Miyano, Hideki Makishima, Yukitsugu Nakamura, Yuka Nakamura, Motoshi Ichikawa, Seishi Ogawa

BLOOD 128 ( 24 ) 2863 - 2866 2016年12月

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記述言語：英語出版者・発行元：AMER SOC HEMATOLOGY

DOI： 10.1182/blood-2016-06-723494

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Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. 査読

Madan V, Shyamsunder P, Han L, Mayakonda A, Nagata Y, Sundaresan J, Kanojia D, Yoshida K, Ganesan S, Hattori N, Fulton N, Tan KT, Alpermann T, Kuo MC, Rostami S, Matthews J, Sanada M, Liu LZ, Shiraishi Y, Miyano S, Chendamarai E, Hou HA, Malnassy G, Ma T, Garg M, Ding LW, Sun QY, Chien W, Ikezoe T, Lill M, Biondi A, Larson RA, Powell BL, Lübbert M, Chng WJ, Tien HF, Heuser M, Ganser A, Koren-Michowitz M, Kornblau SM, Kantarjian HM, Nowak D, Hofmann WK, Yang H, Stock W, Ghavamzadeh A, Alimoghaddam K, Haferlach T, Ogawa S, Shih LY, Mathews V, Koeffler HP

Leukemia 30 ( 12 ) 2430 2016年12月

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DOI： 10.1038/leu.2016.237

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Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia 査読

Sun Qiao-Yang, Ding Ling-wen, Tan Kar-Tong, Chien Wenwen, Mayakonda Anand, Yeoh Allen Eng Juh, Kawamata Norihiko, Nagata Yasunobu, Xiao Jin-Fen, Loh Xin-Yi, Lin De-Chen, Garg Manoj, Jiang Yan-Yi, Xu Liang, Lim Su-Lin, Liu Li-Zhen, Madan Vikas, Sanada Masashi, Fernandez Lucia Torres, Preethi Hema S. S, Lill Michael, Kantarjian Hagop M, Kornblau Steven M, Miyano Satoru, Liang Der-Cherng, Ogawa Seishi, Shih Lee-Yung, Yang Henry, Koeffler H. Phillip

BLOOD 128 ( 22 ) 2016年12月

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記述言語：英語

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Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia 査読

Norio Shiba, Kenichi Yoshida, Yuichi Shiraishi, Yusuke Okuno, Genki Yamato, Yusuke Hara, Yasunobu Nagata, Kenichi Chiba, Hiroko Tanaka, Kiminori Terui, Motohiro Kato, Myoung-ja Park, Kentaro Ohki, Akira Shimada, Junko Takita, Daisuke Tomizawa, Kazuko Kudo, Hirokazu Arakawa, Souichi Adachi, Takashi Taga, Akio Tawa, Etsuro Ito, Keizo Horibe, Masashi Sanada, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi

BRITISH JOURNAL OF HAEMATOLOGY 175 ( 3 ) 476 - 489 2016年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (83%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (83%), BCOR/BCORL1 in 7 patients (34%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence.

DOI： 10.1111/bjh.14247

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Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms 査読

T. Mori, Y. Nagata, H. Makishima, M. Sanada, Y. Shiozawa, A. Kon, T. Yoshizato, A. Sato-Otsubo, K. Kataoka, Y. Shiraishi, K. Chiba, H. Tanaka, K. Ishiyama, S. Miyawaki, H. Mori, T. Nakamaki, R. Kihara, H. Kiyoi, H. P. Koeffler, L-Y Shih, S. Miyano, T. Naoe, C. Haferlach, W. Kern, T. Haferlach, S. Ogawa, K. Yoshida

LEUKEMIA 30 ( 11 ) 2270 - 2273 2016年11月

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記述言語：英語出版者・発行元：NATURE PUBLISHING GROUP

DOI： 10.1038/leu.2016.212

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Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia 査読

V. Madan, P. Shyamsunder, L. Han, A. Mayakonda, Y. Nagata, J. Sundaresan, D. Kanojia, K. Yoshida, S. Ganesan, N. Hattori, N. Fulton, K. T. Tan, T. Alpermann, M. C. Kuo, S. Rostami, J. Matthews, M. Sanada, L. Z. Liu, Y. Shiraishi, S. Miyano, E. Chendamarai, H. A. Hou, G. Malnassy, T. Ma, M. Garg, L. W. Ding, Q. Y. Sun, W. Chien, T. Ikezoe, M. Lill, A. Biondi, R. A. Larson, B. L. Powell, M. Lübbert, W. J. Chng, H. F. Tien, M. Heuser, A. Ganser, M. Koren-Michowitz, S. M. Kornblau, H. M. Kantarjian, D. Nowak, W. K. Hofmann, H. Yang, W. Stock, A. Ghavamzadeh, K. Alimoghaddam, T. Haferlach, S. Ogawa, L. Y. Shih, V. Mathews, H. P. Koeffler

Leukemia 30 ( 8 ) 1672 - 1681 2016年8月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Publishing Group

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15
17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

DOI： 10.1038/leu.2016.69

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Aberrant PD-L1 expression through 3 '-UTR disruption in multiple cancers 査読

Keisuke Kataoka, Yuichi Shiraishi, Yohei Takeda, Seiji Sakata, Misako Matsumoto, Seiji Nagano, Takuya Maeda, Yasunobu Nagata, Akira Kitanaka, Seiya Mizuno, Hiroko Tanaka, Kenichi Chiba, Satoshi Ito, Yosaku Watatani, Nobuyuki Kakiuchi, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Masashi Sanada, Hidehiro Itonaga, Yoshitaka Imaizumi, Yasushi Totoki, Wataru Munakata, Hiromi Nakamura, Natsuko Hama, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Takuro Kameda, Kyoko Masuda, Nagahiro Minato, Koichi Kashiwase, Koji Izutsu, Akifumi Takaori-Kondo, Yasushi Miyazaki, Satoru Takahashi, Tatsuhiro Shibata, Hiroshi Kawamoto, Yoshiki Akatsuka, Kazuya Shimoda, Kengo Takeuchi, Tsukasa Seya, Satoru Miyano, Seishi Ogawa

NATURE 534 ( 7607 ) 402 - + 2016年6月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development(1-6). However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma(6-10). Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.

DOI： 10.1038/nature18294

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GENETIC LANDSCAPE OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

K. Yoshida, K. Chiba, Y. Okuno, N. Kakiuchi, S. Suzuki, H. Suzuki, R. Nakamoto-Matsubara, S. Koriyama, Y. Shiraishi, T. Yoshizato, Y. Shiozawa, K. Kataoka, H. Ueno, Y. Nagata, Y. Sato, H. Tanaka, A. Hayano, J. Homma, J. Fukai, K. Kajiwara, M. Ideguchi, Y. Komohara, N. Yajima, N. Tsuchiya, M. Sano, M. Nitta, Y. Muragaki, M. Sakata-Yanagimoto, Y. Iwadate, H. Hondoh, K. Kashiwase, T. Shiina, S. Miyano, S. Chiba, R. Yamanaka, S. Ogawa

HAEMATOLOGICA 101 ( 1 ) 179 - 179 2016年6月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：FERRATA STORTI FOUNDATION

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Variegated RHOA mutations in adult T-cell leukemia/lymphoma 査読

Yasunobu Nagata, Kenji Kontani, Terukazu Enami, Keisuke Kataoka, Ryohei Ishii, Yasushi Totoki, Tatsuki R. Kataoka, Masahiro Hirata, Kazuhiro Aoki, Kazumi Nakano, Akira Kitanaka, Mamiko Sakata-Yanagimoto, Sachiko Egami, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Yusuke Shiozawa, Tetsuichi Yoshizato, Hiromichi Suzuki, Ayana Kon, Kenichi Yoshida, Yusuke Sato, Aiko Sato-Otsubo, Masashi Sanada, Wataru Munakata, Hiromi Nakamura, Natsuko Hama, Satoru Miyano, Osamu Nureki, Tatsuhiro Shibata, Hironori Haga, Kazuya Shimoda, Toshiaki Katada, Shigeru Chiba, Toshiki Watanabe, Seishi Ogawa

BLOOD 127 ( 5 ) 596 - 604 2016年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC HEMATOLOGY

Adult T-cell leukemia/lymphoma (ATLL) is a distinct form of peripheral T-cell lymphoma with poor prognosis, which is caused by the human T-lymphotropic virus type 1 (HTLV-1). In contrast to the unequivocal importance of HTLV-1 infection in the pathogenesis of ATLL, the role of acquired mutations in HTLV-1 infected T cells has not been fully elucidated, with a handful of genes known to be recurrently mutated. In this study, we identified unique RHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations were widely distributed across the entire coding sequence but almost invariably located at the guanosine triphosphate (GTP)-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/guanosine diphosphate (GDP)-binding kinetics, regulation of actin fibers, and transcriptional activation. The Gly17Val mutant did not bind GTP/GDP and act as a dominant negative molecule, whereas other mutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss-and gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers.

DOI： 10.1182/blood-2015-06-644948

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Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution 査読

Ryutaro Uchi, Yusuke Takahashi, Atsushi Niida, Teppei Shimamura, Hidenari Hirata, Keishi Sugimachi, Genta Sawada, Takeshi Iwaya, Junji Kurashige, Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi, Kenichi Chiba, Yuichi Shiraishi, Genta Nagae, Kenichi Yoshida, Yasunobu Nagata, Hiroshi Haeno, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Hisae Iinuma, Shin Sasaki, Satoshi Nagayama, Kazutaka Yamada, Shinichi Yachida, Mamoru Kato, Tatsuhiro Shibata, Eiji Oki, Hiroshi Saeki, Ken Shirabe, Yoshinao Oda, Yoshihiko Maehara, Shizuo Komune, Masaki Mori, Yutaka Suzuki, Ken Yamamoto, Hiroyuki Aburatani, Seishi Ogawa, Satoru Miyano, Koshi Mimori

PLOS GENETICS 12 ( 2 ) e1005778 2016年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

DOI： 10.1371/journal.pgen.1005778

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Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution. 査読国際誌

Ryutaro Uchi, Yusuke Takahashi, Atsushi Niida, Teppei Shimamura, Hidenari Hirata, Keishi Sugimachi, Genta Sawada, Takeshi Iwaya, Junji Kurashige, Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi, Kenichi Chiba, Yuichi Shiraishi, Genta Nagae, Kenichi Yoshida, Yasunobu Nagata, Hiroshi Haeno, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Hisae Iinuma, Shin Sasaki, Satoshi Nagayama, Kazutaka Yamada, Shinichi Yachida, Mamoru Kato, Tatsuhiro Shibata, Eiji Oki, Hiroshi Saeki, Ken Shirabe, Yoshinao Oda, Yoshihiko Maehara, Shizuo Komune, Masaki Mori, Yutaka Suzuki, Ken Yamamoto, Hiroyuki Aburatani, Seishi Ogawa, Satoru Miyano, Koshi Mimori

PLoS genetics 12 ( 2 ) e1005778 2016年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

DOI： 10.1371/journal.pgen.1005778

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Next-Generation Sequencing Reveal Proviral Genome and Transcriptome in Adult T-Cell Leukemia/Lymphoma 査読

Kataoka Keisuke, Nagata Yasunobu, Kitanaka Akira, Shiraishi Yuichi, Totoki Yasushi, Yasunaga Junichirou, Chiba Kenichi, Sato-Otsubo Aiko, Sanada Masashi, Tanaka Hiroko, Shiozawa Yusuke, Yoshizato Tetsuichi, Yoshida Kenichi, Makishima Hideki, Hishizawa Masakatsu, Itonaga Hidehiro, Imaizumi Yoshitaka, Munakata Wataru, Hiromi Nakamura, Hama Natsuko, Shide Kotaro, Kubuki Yoko, Hidaka Tomonori, Kameda Takuro, Nakamaki Tsuyoshi, Tobinai Kensei, Miyazaki Yasushi, Takaori-Kondo Akifumi, Matsuoka Masao, Shibata Tatsuhiro, Miyano Satoru, Shimoda Kazuya, Ogawa Seishi

BLOOD 126 ( 23 ) 2015年12月

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Frequent Activating Somatic Alterations in T-Cell Receptor/NF-kappa b Signaling in Adult T-Cell Leukemia/Lymphoma 査読

Kataoka Keisuke, Nagata Yasunobu, Kitanaka Akira, Shiraishi Yuichi, Yasunaga Jun-ichirou, Totoki Yasushi, Chiba Kenichi, Sato-Otsubo Aiko, Kotani Shinichi, Sanada Masashi, Tanaka Hiroko, Suzuki Hiromichi, Sato Yusuke, Shiozawa Yusuke, Yoshizato Tetsuichi, Yoshida Kenichi, Makishima Hideki, Ma Guangyong, Nosaka Kisato, Hishizawa Masakatsu, Itonaga Hidehiro, Imaizumi Yoshitaka, Munakata Wataru, Hiromi Nakamura, Hama Natsuko, Shide Kotaro, Kubuki Yoko, Hidaka Tomonori, Kameda Takuro, Nakamaki Tsuyoshi, Ishiyama Ken, Miyawaki Shuichi, Tobinai Kensei, Miyazaki Yasushi, Takaori-Kondo Akifumi, Watanabe Toshiki, Shibata Tatsuhiro, Matsuoka Masao, Miyano Satoru, Shimoda Kazuya, Ogawa Seishi

BLOOD 126 ( 23 ) 2015年12月

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Landscape of DNA Methylation and Genetic Profiles in 291 Patients with Myelodysplastic Syndromes 査読

Nagata Yasunobu, Suzuki Hiromichi, Grossmann Vera, Nagae Genta, Okuno Yusuke, Bacher Ulrike, Schnittger Susanne, Shiozawa Yusuke, Yoshizato Tetsuichi, Alpermann Tamara, Yoshida Kenichi, Kataoka Keisuke, Nadarajah Niroshan, Roller Andreas, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Kohlmann Alexander, Haferlach Claudia, Sato Tsutomu, Hirase Chikara, Dobashi Nobuaki, Kiguchi Toru, Chiba Shigeru, Ohtake Shigeki, Kiyoi Hitoshi, Kobayashi Yukio, Naoe Tomoki, Miyano Satoru, Kern Wolfgang, Makishima Hideki, Aburatani Hiroyuki, Miyazaki Yasushi, Haferlach Torsten, Ogawa Seishi

BLOOD 126 ( 23 ) 2015年12月

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Genomic landscape of liposarcoma 査読

Deepika Kanojia, Yasunobu Nagata, Manoj Garg, Dhong Hyun Lee, Aiko Sato, Kenichi Yoshida, Yusuke Sato, Masashi Sanada, Anand Mayakonda, Christoph Bartenhagen, Hans-Ulrich Klein, Ngan B. Doan, Jonathan W. Said, S. Mohith, Swetha Gunasekar, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Ola Myklebost, Henry Yang, Martin Dugas, Leonardo A. Meza-Zepeda, Allan W. Silberman, Charles Forscher, Jeffrey W. Tyner, Seishi Ogawa, H. Phillip Koeffler

ONCOTARGET 6 ( 40 ) 42429 - 42444 2015年12月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：IMPACT JOURNALS LLC

Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK-STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.

DOI： 10.18632/oncotarget.6464

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Genetic Basis of Primary Central Nervous System Lymphoma

Kenichi Yoshida, Rie Nakamoto-Matsubara, Kenichi Chiba, Yusuke Okuno, Nobuyuki Kakiuchi, Yuichi Shiraishi, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Yusuke Shiozawa, Keisuke Kataoka, Hiroo Ueno, June Takeda, Yasunobu Nagata, Hiroko Tanaka, Yasuo Iwadate, Hiroaki Hondoh, Junya Fukai, Koji Kajiwara, Makoto Idegechi, Yoshihiro Komohara, Yukihiko Fujii, Syunichi Kohriyama, Masayuki Nitta, Yoshiharu Muragaki, Mamiko Sakata-Yanagimoto, Shingo Suzuki, Takashi Shiina, Satoru Miyano, Shigeru Chiba, Yamanaka Ryuya, Seishi Ogawa

BLOOD 126 ( 23 ) 2015年12月

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記述言語：英語出版者・発行元：AMER SOC HEMATOLOGY

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Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse 査読

Manoj Garg, Yasunobu Nagata, Deepika Kanojia, Anand Mayakonda, Kenichi Yoshida, Sreya Haridas Keloth, Zhi Jiang Zang, Yusuke Okuno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Ling-Wen Ding, Tamara Alpermann, Qiao-Yang Sun, De-Chen Lin, Wenwen Chien, Vikas Madan, Li-Zhen Liu, Kar-Tong Tan, Abhishek Sampath, Subhashree Venkatesan, Koiti Inokuchi, Satoshi Wakita, Hiroki Yamaguchi, Wee Joo Chng, Shirley-Kow Yin Kham, Allen Eng-Juh Yeoh, Masashi Sanada, Joanna Schiller, Karl-Anton Kreuzer, Steven M. Kornblau, Hagop M. Kantarjian, Torsten Haferlach, Michael Lill, Ming-Chung Kuo, Lee-Yung Shih, Igor-Wolfgang Blau, Olga Blau, Henry Yang, Seishi Ogawa, H. Phillip Koeffler

BLOOD 126 ( 22 ) 2491 - 2501 2015年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC HEMATOLOGY

Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.

DOI： 10.1182/blood-2015-05-646240

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Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms 査読

R. J. Molenaar, S. Thota, Y. Nagata, B. Patel, M. Clemente, B. Przychodzen, C. Hirsh, A. D. Viny, N. Hosano, F. E. Bleeker, M. Meggendorfer, T. Alpermann, Y. Shiraishi, K. Chiba, H. Tanaka, C. J. F. van Noorden, T. Radivoyevitch, H. E. Carraway, H. Makishima, S. Miyano, M. A. Sekeres, S. Ogawa, T. Haferlach, J. P. Maciejewski

LEUKEMIA 29 ( 11 ) 2134 - 2142 2015年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Mutations in isocitrate dehydrogenase 1/2 (IDH1/2(MT)) are drivers of a variety of myeloid neoplasms. As they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent, and pooled. We studied the validity of this approach and found IDH1/2 mutations in 179 of 2119 myeloid neoplasms (8%). Cross-sectionally, the frequencies of these mutations increased from lower-to higher risk disease, thus suggesting a role in clinical progression. Variant allelic frequencies indicated that IDH1(MT) and IDH2(MT) are ancestral in up to 14/74 (19%) vs 34/99 (34%; P = 0.027) of cases, respectively, illustrating the pathogenic role of these lesions in myeloid neoplasms. IDH1/2(MT) was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1(MT) cases were associated with a worse prognosis than subclonal IDH1(MT) cases, whereas the position of IDH2(MT) within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1(MT) cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2(MT) cases. Our data demonstrate important clinical and biological differences between IDH1(MT) and IDH2(MT) myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2(MT) inhibitors of IDH1/2(MT) patients.

DOI： 10.1038/leu.2015.91

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Integrated molecular analysis of adult T cell leukemia/lymphoma 査読

Keisuke Kataoka, Yasunobu Nagata, Akira Kitanaka, Yuichi Shiraishi, Teppei Shimamura, Jun-Ichirou Yasunaga, Yasushi Totoki, Kenichi Chiba, Aiko Sato-Otsubo, Genta Nagae, Ryohei Ishii, Satsuki Muto, Shinichi Kotani, Yosaku Watatani, June Takeda, Masashi Sanada, Hiroko Tanaka, Hiromichi Suzuki, Yusuke Sato, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masako Iwanaga, Guangyong Ma, Kisato Nosaka, Masakatsu Hishizawa, Hidehiro Itonaga, Yoshitaka Imaizumi, Wataru Munakata, Hideaki Ogasawara, Toshitaka Sato, Ken Sasai, Kenzo Muramoto, Marina Penova, Takahisa Kawaguchi, Hiromi Nakamura, Natsuko Hama, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Takuro Kameda, Tsuyoshi Nakamaki, Ken Ishiyama, Shuichi Miyawaki, Sung-Soo Yoon, Kensei Tobinai, Yasushi Miyazaki, Akifumi Takaori-Kondo, Fumihiko Matsuda, Kengo Takeuchi, Osamu Nureki, Hiroyuki Aburatani, Toshiki Watanabe, Tatsuhiro Shibata, Masao Matsuoka, Satoru Miyano, Kazuya Shimoda, Seishi Ogawa

NATURE GENETICS 47 ( 11 ) 1304 - + 2015年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-kappa B signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

DOI： 10.1038/ng.3415

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骨髄異形成症候群(MDS)288例における網羅的DNAメチル化解析と標的遺伝子異常との統合解析

永田安伸, 永江玄太, 鈴木啓道, 吉田健一, 片岡圭亮, 塩澤裕介, 白石友一, 千葉健一, 眞田昌, 宮野悟, 牧島秀樹, 油谷浩幸, 小川誠司

日本癌学会総会記事 74回 E - 1153 2015年10月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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BRCC3 mutations in myeloid neoplasms 査読

Dayong Huang, Yasunobu Nagata, Vera Grossmann, Tomas Radivoyevitch, Yusuke Okuno, Genta Nagae, Naoko Hosono, Susanne Schnittger, Masashi Sanada, Bartlomiej Przychodzen, Ayana Kon, Chantana Polprasert, Wenyi Shen, Michael J. Clemente, James G. Phillips, Tamara Alpermann, Kenichi Yoshida, Niroshan Nadarajah, Mikkael A. Sekeres, Kevin Oakley, Nhu Nguyen, Yuichi Shiraishi, Yusuke Shiozawa, Kenichi Chiba, Hiroko Tanaka, H. Phillip Koeffler, Hans-Ulrich Klein, Martin Dugas, Hiroyuki Aburatani, Satoru Miyano, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, Yang Du, Seishi Ogawa, Hideki Makishima

HAEMATOLOGICA 100 ( 8 ) 1051 - 1057 2015年8月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：FERRATA STORTI FOUNDATION

Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority of mutations (n=23; 82%) were hemizygous. Phenotypically, BRCC3 mutations were frequently observed in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms and associated with -Y abnormality (odds ratio; 3.70, 1.25-11.0). Clinically, BRCC3 mutations were also related to higher age (P=0.01), although prognosis was not affected. Knockdown of Brcc3 gene expression in murine bone marrow lineage negative, Sca1 positive, c-kit positive cells resulted in 2-fold more colony formation and modest differentiation defect. Thus, BRCC3 likely plays a role as tumor-associated gene in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.

DOI： 10.3324/haematol.2014.111989

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Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia 査読

T. Yoshizato, B. Dumitriu, K. Hosokawa, H. Makishima, K. Yoshida, D. Townsley, A. Sato-Otsubo, Y. Sato, D. Liu, H. Suzuki, C. O. Wu, Y. Shiraishi, M. J. Clemente, K. Kataoka, Y. Shiozawa, Y. Okuno, K. Chiba, H. Tanaka, Y. Nagata, T. Katagiri, A. Kon, M. Sanada, P. Scheinberg, S. Miyano, J. P. Maciejewski, S. Nakao, N. S. Young, S. Ogawa

NEW ENGLAND JOURNAL OF MEDICINE 373 ( 1 ) 35 - 47 2015年7月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MASSACHUSETTS MEDICAL SOC

BACKGROUND
In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia.
METHODS
We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients.
RESULTS
Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients.
CONCLUSIONS
Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.)

DOI： 10.1056/NEJMoa1414799

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Mutational landscape and clonal architecture in grade II and III gliomas 査読

Hiromichi Suzuki, Kosuke Aoki, Kenichi Chiba, Yusuke Sato, Yusuke Shiozawa, Yuichi Shiraishi, Teppei Shimamura, Atsushi Niida, Kazuya Motomura, Fumiharu Ohka, Takashi Yamamoto, Kuniaki Tanahashi, Melissa Ranjit, Toshihiko Wakabayashi, Tetsuichi Yoshizato, Keisuke Kataoka, Kenichi Yoshida, Yasunobu Nagata, Aiko Sato-Otsubo, Hiroko Tanaka, Masashi Sanada, Yutaka Kondo, Hideo Nakamura, Masahiro Mizoguchi, Tatsuya Abe, Yoshihiro Muragaki, Reiko Watanabe, Ichiro Ito, Satoru Miyano, Atsushi Natsume, Seishi Ogawa

NATURE GENETICS 47 ( 5 ) 458 - U52 2015年5月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive and negative correlations and a chronological hierarchy, as inferred from different allelic burdens among coexisting mutations, suggesting that there is functional interplay between the mutations that drive clonal selection. Extensive serial and multi-regional sampling analyses further supported this finding and also identified a high degree of temporal and spatial heterogeneity generated during tumor expansion and relapse, which is likely shaped by the complex but ordered processes of multiple clonal selection and evolutionary events.

DOI： 10.1038/ng.3273

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Establishment and Characterization of Novel Human Primary and Metastatic Anaplastic Thyroid Cancer Cell Lines and Their Genomic Evolution Over a Year as a Primagraft 査読

Manoj Garg, Ryoko Okamoto, Yasunobu Nagata, Deepika Kanojia, Subhashree Venkatesan, M. T. Anand, Glenn D. Braunstein, Jonathan W. Said, Ngan B. Doan, Quoc Ho, Tadayuki Akagi, Sigal Gery, Li-zhen Liu, Kar Tong Tan, Wee Joo Chng, Henry Yang, Seishi Ogawa, H. Phillip Koeffler

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 100 ( 2 ) 725 - 735 2015年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ENDOCRINE SOC

Context: Anaplastic thyroid cancer (ATC) has no effective treatment, resulting in a high rate of mortality. We established cell lines from a primary ATC and its lymph node metastasis, and investigated the molecular factors and genomic changes associated with tumor growth.
Objective: The aim of the study was to understand the molecular and genomic changes of highly aggressive ATC and its clonal evolution to develop rational therapies.
Design: We established unique cell lines from primary (OGK-P) and metastatic (OGK-M) ATC specimen, as well as primagraft from the metastatic ATC, which was serially xeno-transplanted for more than 1 year in NOD scid gamma mice were established. These cell lines and primagraft were used as tools to examine gene expression, copy number changes, and somatic mutations using RNA array, SNP Chip, and whole exome sequencing.
Results: Mice carrying sc (OGK-P and OGK-M) tumors developed splenomegaly and neutrophilia with high expression of cytokines including CSF1, CSF2, CSF3, IL-1 beta, and IL-6. Levels of HIF-1 alpha and its targeted genes were also elevated in these tumors. The treatment of tumor carrying mice with Bevacizumab effectively decreased tumor growth, macrophage infiltration, and peripheral WBCs. SNP chip analysis showed homozygous deletion of exons 3-22 of the PARD3 genein the cells. Forced expression of PARD3 decreased cell proliferation, motility, and invasiveness, restores cell-cell contacts and enhanced cell adhesion. Next generation exome sequencing identified the somatic changes present in the primary, metastatic, and primagraft tumors demonstrating evolution of the mutational signature over the year of passage in vivo.
Conclusion: To our knowledge, we established the first paired human primary and metastatic ATC cell lines offering unique possibilities for comparative functional investigations in vitro and in vivo. Our exome sequencing also identified novel mutations, as well as clonal evolution in both the metastasis and primagraft.

DOI： 10.1210/jc.2014-2359

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Genomon ITDetector: a tool for somatic internal tandem duplication detection from cancer genome sequencing data 査読

Kenichi Chiba, Yuichi Shiraishi, Yasunobu Nagata, Kenichi Yoshida, Seiya Imoto, Seishi Ogawa, Satoru Miyano

BIOINFORMATICS 31 ( 1 ) 116 - 118 2015年1月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Somatic internal tandem duplications (ITDs) are known to play important roles in cancer pathogenesis. Although recent advances in high-throughput sequencing technologies have enabled genome-wide detection of various types of genomic mutations, including single nucleotide variants, indels and structural variations, only a few studies have focused on ITDs. We have developed an analytical tool called 'Genomon ITDetector' for genome-wide detection of somatic ITDs. After evaluating the sensitivity and precision of the proposed approach using synthetic data, we have demonstrated that it can successfully detect not only common ITDs involving FLT3, but also a number of ITDs affecting other putative driver genes in acute myeloid leukemia exome sequencing data.

DOI： 10.1093/bioinformatics/btu593

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Novel Biological Effects and Distinct Patterns of Rhoa Mutations in Adult T-Cell Leukemia/Lymphoma and Angioimmunoblastic T Cell Lymphoma

Nagata,Yasunobu, Enami,Terukazu, Kontani,Kenji, Kataoka,Keisuke, Sakata-Yanagimoto,Mamiko, Kitanaka,Akira, Sato,Aiko, Shiraishi,Yuichi, Chiba,Kenichi, Tanaka,Hiroko, Shiozawa,Yusuke, Yoshizato,Tetsuichi, Kon,Ayana, Yoshida,Kenichi, Sanada,Masashi, Ishiyama,Ken, Miyawaki,Shuichi, Ishii,Ryohei, Nureki,Osamu, Miyano,Satoru, Shimoda,Kazuya, Watanabe,Toshiki, Katada,Toshiaki, Chiba,Shigeru, Ogawa,Seishi

BLOOD 124 ( 21 ) 2014年12月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC HEMATOLOGY

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Landscape of Genetic Alterations in Adult T-Cell Leukemia/Lymphoma 査読

Keisuke Kataoka, Yasunobu Nagata, Akira Kitanaka, Yasushi Totoki, Jun-Ichirou Yasunaga, Shinichi Kotani, Aiko Sato-Otsubo, Masashi Sanada, Yuichi Shiraishi, Teppei Shimamura, Kenichi Chiba, Hiroko Tanaka, Hiromichi Suzuki, Yusuke Sato, Yusuke Shiozawa, Tetsuichi Yoshizato, Ayana Kon, Kenichi Yoshida, Masakatsu Hishizawa, Wataru Munakata, Hiromi Nakamura, Natsuko Hama, Kotaro Shide, Yoko Kubuki, Tomonari Hidaka, Takuro Kameda, Ken Ishiyama, Shuichi Miyawaki, Ryohei Ishii, Osamu Nureki, Genta Nagae, Hiroyuki Aburatani, Satoru Miyano, Akifumi Takaori-Kondo, Toshiki Watanabe, Masao Matsuoka, Tatsuhiro Shibata, Kazuya Shimoda, Seishi Ogawa

BLOOD 124 ( 21 ) 2014年12月

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記述言語：英語出版者・発行元：AMER SOC HEMATOLOGY

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Expressional changes of genes and miRNA in common megakaryocyte-erythroid progenitors from lower-risk myelodysplastic syndrome 査読

Kazuhiro Maki, Ko Sasaki, Yasunobu Nagata, Fusako Nagasawa, Yuka Nakamura, Seishi Ogawa, Kinuko Mitani

INTERNATIONAL JOURNAL OF HEMATOLOGY 100 ( 4 ) 361 - 369 2014年10月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER JAPAN KK

Myelodysplastic syndrome (MDS) is a stem cell tumor characterized by dysplastic features and ineffective hematopoiesis in the early phase and leukemic progression in the late phase. Speculating that differences in the expression of genes and microRNA (miRNA) in control and MDS-derived erythroid progenitors may cause ineffective erythropoiesis, we sorted common megakaryocyte-erythroid progenitors (MEPs) in bone marrow cells from three lower-risk MDS patients, and compared expression levels of genes and miRNA with those from controls. In apoptosis-related pathways, the expression of some pro-apoptotic genes, such as cell death-inducing DFFA-like effector A, caspase 5, and Fas ligand, was elevated in MDS-derived MEPs, while those of anti-apoptotic CD40 and tumor necrosis factor were lower. In hematopoiesis-regulating pathways, RUNX1 and ETV6 genes showed reduced expression. Expression profiling revealed that three and 35 miRNAs were significantly up- and down-regulated in MDS-derived MEPs. MIR9 exhibited robust expression in MEPs and CD71+GlyA+ erythroid cells derived from one of the three patients. Interestingly, overexpression of MIR9 inhibited the accumulation of hemoglobin in UT-7/GM cells. Some of these alterations in gene and miRNA expression may contribute to the pathogenesis of ineffective hematopoiesis in lower-risk MDS and provide molecular markers for sub-classification and making a prognosis.

DOI： 10.1007/s12185-014-1639-2

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A robust molecular pattern for myelodysplastic syndromes in two independent cohorts investigated by next-generation sequencing can be revealed by comparative bioinformatic analyses 査読

Dominic Rose, Alexander Kohlmann, Yasunobu Nagata, Seishi Ogawa, Claudia Haferlach, Wolfgang Kern, Susanne Schnittger, Torsten Haferlach

BRITISH JOURNAL OF HAEMATOLOGY 167 ( 2 ) 278 - 281 2014年10月

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記述言語：英語出版者・発行元：WILEY-BLACKWELL

DOI： 10.1111/bjh.12971

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骨髄系腫瘍541例におけるPHF6異常の解明

森拓人, 永田安伸, 吉田健一, 塩澤祐介, 吉里哲一, 昆彩奈, 佐藤亜以子, 白石友一, 千葉健一, 田中洋子, 片岡圭亮, 眞田昌, 中牧剛, 石山謙, 宮脇修一, 森啓, 宮野悟, ケフェラー・フィリップ, シー・リーユン, 小川誠司

臨床血液 55 ( 9 ) 1296 - 1296 2014年9月

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記述言語：日本語出版者・発行元：(一社)日本血液学会-東京事務局

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Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients 査読

R. Kihara, Y. Nagata, H. Kiyoi, T. Kato, E. Yamamoto, K. Suzuki, F. Chen, N. Asou, S. Ohtake, S. Miyawaki, Y. Miyazaki, T. Sakura, Y. Ozawa, N. Usui, H. Kanamori, T. Kiguchi, K. Imai, N. Uike, F. Kimura, K. Kitamura, C. Nakaseko, M. Onizuka, A. Takeshita, F. Ishida, H. Suzushima, Y. Kato, H. Miwa, Y. Shiraishi, K. Chiba, H. Tanaka, S. Miyano, S. Ogawa, T. Naoe

LEUKEMIA 28 ( 8 ) 1586 - 1595 2014年8月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

DOI： 10.1038/leu.2014.55

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The genomic landscape of nasopharyngeal carcinoma 査読

De-Chen Lin, Xuan Meng, Masaharu Hazawa, Yasunobu Nagata, Ana Maria Varela, Liang Xu, Yusuke Sato, Li-Zhen Liu, Ling-Wen Ding, Arjun Sharma, Boon Cher Goh, Soo Chin Lee, Bengt Fredrik Petersson, Feng Gang Yu, Paul Macary, Min Zin Oo, Chan Soh Ha, Henry Yang, Seishi Ogawa, Kwok Seng Loh, H. Phillip Koeffler

NATURE GENETICS 46 ( 8 ) 866 - 871 2014年8月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.

DOI： 10.1038/ng.3006

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DISTINCT PATTERNS OF RHOA MUTATIONS IN ADULT T-CELL LEUKEMIA/LMPHOMA AND OTHER PERIPHERAL T-CELL LYMPHOMAS

Kataoka,K, Yasunobu,N, Enami,T, Kitanaka,A, Sakata-Yanagimoto,M, Sanada,M, Sato,A, Shiraishi,Y, Chiba,K, Tanaka,H, Yoshizato,T, Kon,A, Yoshida,K, Ishiyama,K, Miyawaki,S, Miyano,S, Chiba,S, Shimoda,K, Watanabe,T, Ogawa,S

HAEMATOLOGICA 99 ( 1 ) 503 - 504 2014年6月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：FERRATA STORTI FOUNDATION

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Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome 査読

Yusuke Sato, Shigekatsu Maekawa, Ryohei Ishii, Masashi Sanada, Teppei Morikawa, Yuichi Shiraishi, Kenichi Yoshida, Yasunobu Nagata, Aiko Sato-Otsubo, Tetsuichi Yoshizato, Hiromichi Suzuki, Yusuke Shiozawa, Keisuke Kataoka, Ayana Kon, Kosuke Aoki, Kenichi Chiba, Hiroko Tanaka, Haruki Kume, Satoru Miyano, Masashi Fukayama, Osamu Nureki, Yukio Homma, Seishi Ogawa

SCIENCE 344 ( 6186 ) 917 - 920 2014年5月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC ADVANCEMENT SCIENCE

Cushing's syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing's syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing's syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing's syndrome, providing insights into the diagnosis and therapeutics of this syndrome.

DOI： 10.1126/science.1252328

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Genomic and molecular characterization of esophageal squamous cell carcinoma 査読

De-Chen Lin, Jia-Jie Hao, Yasunobu Nagata, Liang Xu, Li Shang, Xuan Meng, Yusuke Sato, Yusuke Okuno, Ana Maria Varela, Ling-Wen Ding, Manoj Garg, Li-Zhen Liu, Henry Yang, Dong Yin, Zhi-Zhou Shi, Yan-Yi Jiang, Wen-Yue Gu, Ting Gong, Yu Zhang, Xin Xu, Ori Kalid, Sharon Shacham, Seishi Ogawa, Ming-Rong Wang, H. Phillip Koeffler

NATURE GENETICS 46 ( 5 ) 467 - 473 2014年5月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Esophageal squamous cell carcinoma (ESCC) is prevalent worldwide and particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified previously uncharacterized mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to those already known (TP53, PIK3CA and NOTCH 1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Our approaches also uncovered many druggable candidates, and XPO1 was further explored as a therapeutic target because it showed both gene mutation and protein overexpression. Our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.

DOI： 10.1038/ng.2935

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Landscape of genetic lesions in 944 patients with myelodysplastic syndromes 査読

T. Haferlach, Y. Nagata, V. Grossmann, Y. Okuno, U. Bacher, G. Nagae, S. Schnittger, M. Sanada, A. Kon, T. Alpermann, K. Yoshida, A. Roller, N. Nadarajah, Y. Shiraishi, Y. Shiozawa, K. Chiba, H. Tanaka, H. P. Koeffler, H-U Klein, M. Dugas, H. Aburatani, A. Kohlmann, S. Miyano, C. Haferlach, W. Kern, S. Ogawa

LEUKEMIA 28 ( 2 ) 241 - 247 2014年2月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in > 10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P < 0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P < 0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P < 0.001). Both models were reproducible in the validation cohort (n = 175 patients; P < 0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.

DOI： 10.1038/leu.2013.336

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Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations 査読

Tung-Liang Lin, Yasunobu Nagata, Hsiao-Wen Kao, Masashi Sanada, Yusuke Okuno, Chein-Fuang Huang, Der-Cherng Liang, Ming-Chung Kuo, Chang-Liang Lai, En-Hui Lee, Yu-Shu Shih, Hiroko Tanaka, Yuichi Shiraishi, Kenichi Chiba, Tung-Huei Lin, Jin-Hou Wu, Satoru Miyano, Seishi Ogawa, Lee-Yung Shih

HAEMATOLOGICA 99 ( 1 ) 28 - 36 2014年1月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：FERRATA STORTI FOUNDATION

Somatic mutations of TET2, IDH1, and IDH2 have been described in myelodysplastic syndrome. The impact of these mutations on outcome of myelodysplastic syndrome and their progression to secondary acute myeloid leukemia remains unclear. Mutation status of TET2, IDH1 and IDH2 was investigated in a cohort of 46 paired myelodysplastic syndrome/acute myeloid leukemia samples and 122 non-paired cases with de novo myelodysplastic syndrome, to clarify their roles in the evolution of myelodysplastic syndrome to acute myeloid leukemia. Among the 168 de novo myelodysplastic syndrome patients, the frequency of TET2, IDH1, and IDH2 mutations was 18.5%, 4.2% and 6.0%, respectively. TET2/IDH mutations had no impact on survivals, while TET2 mutations were significantly associated with rapid progression to acute myeloid leukemia. Seventeen of the 46 paired myelodysplastic syndrome/secondary acute myeloid leukemia samples harbored TET2/IDH mutations; none acquired these mutations in acute myeloid leukemia phase. Progression to acute myeloid leukemia was accompanied by evolution of a novel clone or expansion of a minor pre-existing subclone of one or more distinct mutations in 12 of the 17 cases with TET2/IDH mutations. A minor subclone in 3 cases with biallelic TET2 inactivation subsequently expanded, indicating biallelic TET2 mutations play a role in acute myeloid leukemia progression. Twelve patients acquired other genetic lesions, and/or showed increased relative mutant allelic burden of FLT3-ITD, N/K-RAS, CEBPA or RUNX1 during acute myeloid leukemia progression. Our findings provide a novel insight into the role of TET2/IDH mutation in the pathogenesis of myelodysplastic syndrome and subsequent progression to acute myeloid leukemia.

DOI： 10.3324/haematol.2013.091249

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The landscape of somatic mutations in Down syndrome-related myeloid disorders 査読

Kenichi Yoshida, Tsutomu Toki, Yusuke Okuno, Rika Kanezaki, Yuichi Shiraishi, Aiko Sato-Otsubo, Masashi Sanada, Myoung-ja Park, Kiminori Terui, Hiromichi Suzuki, Ayana Kon, Yasunobu Nagata, Yusuke Sato, RuNan Wang, Norio Shiba, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Hideki Muramatsu, Daisuke Hasegawa, Kazuhiro Nakamura, Hirokazu Kanegane, Keiko Tsukamoto, Souichi Adachi, Kiyoshi Kawakami, Koji Kato, Ryosei Nishimura, Shai Izraeli, Yasuhide Hayashi, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa

NATURE GENETICS 45 ( 11 ) 1293 - + 2013年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).

DOI： 10.1038/ng.2759

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Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders 査読

Tomoya Muto, Goro Sashida, Motohiko Oshima, George R. Wendt, Makiko Mochizuki-Kashio, Yasunobu Nagata, Masashi Sanada, Satoru Miyagi, Atsunori Saraya, Asuka Kamio, Genta Nagae, Chiaki Nakaseko, Koutaro Yokote, Kazuya Shimoda, Haruhiko Koseki, Yutaka Suzuki, Sumio Sugano, Hiroyuki Aburatani, Seishi Ogawa, Atsushi Iwama

JOURNAL OF EXPERIMENTAL MEDICINE 210 ( 12 ) 2627 - 2639 2013年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ROCKEFELLER UNIV PRESS

Polycomb group (PcG) proteins are essential regulators of hematopoietic stem cells. Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). In our patient cohort, EZH2 mutations were also found and often coincided with tet methylcytosine dioxygenase 2 (TET2) mutations. Consistent with these findings, deletion of Ezh2 alone was enough to induce MDS/MPN-like diseases in mice. Furthermore, concurrent depletion of Ezh2 and Tet2 established more advanced myelodysplasia and markedly accelerated the development of myelodysplastic disorders including both MDS and MDS/MPN. Comprehensive genome-wide analyses in hematopoietic progenitor cells revealed that upon deletion of Ezh2, key developmental regulator genes were kept transcriptionally repressed, suggesting compensation by Ezh1, whereas a cohort of oncogenic direct and indirect polycomb targets became derepressed. Our findings provide the first evidence of the tumor suppressor function of EZH2 in myeloid malignancies and highlight the cooperative effect of concurrent gene mutations in the pathogenesis of myelodysplastic disorders.

DOI： 10.1084/jem.20131144

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神経膠腫における全ゲノム/エクソーム解析(Whole genome/exome sequencing reveals landscape of gene mutations in low-grade glioma)

鈴木啓道, 夏目敦至, 佐藤悠佑, 吉田健一, 永田安伸, 白石友一, 大岡史治, 真田昌, 宮野悟, 小川誠司, 若林俊彦

日本癌学会総会記事 72回 84 - 84 2013年10月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders 査読

Frederik Damm, Virginie Chesnais, Yasunobu Nagata, Kenichi Yoshida, Laurianne Scourzic, Yusuke Okuno, Raphael Itzykson, Masashi Sanada, Yuichi Shiraishi, Veronique Gelsi-Boyer, Aline Renneville, Satoru Miyano, Hiraku Mori, Lee-Yung Shih, Sophie Park, Francois Dreyfus, Agnes Guerci-Bresler, Eric Solary, Christian Rose, Stephane Cheze, Thomas Prebet, Norbert Vey, Marion Legentil, Yannis Duffourd, Stephane de Botton, Claude Preudhomme, Daniel Birnbaum, Olivier A. Bernard, Seishi Ogawa, Michaela Fontenay, Olivier Kosmider

BLOOD 122 ( 18 ) 3169 - 3177 2013年10月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC HEMATOLOGY

Patients with low-risk myelodysplastic syndromes (MDS) that rapidly progress to acute myeloid leukemia (AML) remain a challenge in disease management. Using whole-exome sequencing of an MDS patient, we identified a somatic mutation in the BCOR gene also mutated in AML. Sequencing of BCOR and related BCORL1 genes in a cohort of 354 MDS patients identified 4.2% and 0.8% of mutations respectively. BCOR mutations were associated with RUNX1 (P = .002) and DNMT3A mutations (P = .015). BCOR is also mutated in chronic myelomonocytic leukemia patients (7.4%) and BCORL1 in AML patients with myelodysplasia-related changes (9.1%). Using deep sequencing, we show that BCOR mutations arise after mutations affecting genes involved in splicing machinery or epigenetic regulation. In univariate analysis, BCOR mutations were associated with poor prognosis in MDS (overall survival [OS]: P = .013; cumulative incidence of AML transformation: P = .005). Multivariate analysis including age, International Prognostic Scoring System, transfusion dependency, and mutational status confirmed a significant inferior OS to patients with a BCOR mutation (hazard ratio, 3.3; 95% confidence interval, 1.4-8.1; P = .008). These data suggest that BCOR mutations define the clinical course rather than disease initiation. Despite infrequent mutations, BCOR analyses should be considered in risk stratification.

DOI： 10.1182/blood-2012-11-469619

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成人T細胞性白血病/リンパ腫の網羅的遺伝子変異解析(Genetic basis of adult T-cell leukemia/lymphoma)

永田安伸, 北中明, 眞田昌, 佐藤亜以子, 白石友一, 千葉健一, 田中洋子, 吉田健一, 石山謙, 宮脇修一, 宮野悟, 下田和哉, 小川誠司

日本癌学会総会記事 72回 181 - 181 2013年10月

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記述言語：英語出版者・発行元：日本癌学会

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Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. 査読国際誌

Ayana Kon, Lee-Yung Shih, Masashi Minamino, Masashi Sanada, Yuichi Shiraishi, Yasunobu Nagata, Kenichi Yoshida, Yusuke Okuno, Masashige Bando, Ryuichiro Nakato, Shumpei Ishikawa, Aiko Sato-Otsubo, Genta Nagae, Aiko Nishimoto, Claudia Haferlach, Daniel Nowak, Yusuke Sato, Tamara Alpermann, Masao Nagasaki, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Ryo Yamamoto, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Tsuyoshi Nakamaki, Ken Ishiyama, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Shigeru Chiba, Hiraku Mori, Hiromitsu Nakauchi, H Phillip Koeffler, Hiroyuki Aburatani, Torsten Haferlach, Katsuhiko Shirahige, Satoru Miyano, Seishi Ogawa

Nature genetics 45 ( 10 ) 1232 - 7 2013年10月

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記述言語：英語掲載種別：研究論文（学術雑誌）

Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-type RAD21 and wild-type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis.

DOI： 10.1038/ng.2731

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Somatic SETBP1 mutations in myeloid malignancies 査読

Hideki Makishima, Kenichi Yoshida, Nhu Nguyen, Bartlomiej Przychodzen, Masashi Sanada, Yusuke Okuno, Kwok Peng Ng, Kristbjorn O. Gudmundsson, Bandana A. Vishwakarma, Andres Jerez, Ines Gomez-Segui, Mariko Takahashi, Yuichi Shiraishi, Yasunobu Nagata, Kathryn Guinta, Hiraku Mori, Mikkael A. Sekeres, Kenichi Chiba, Hiroko Tanaka, Hideki Muramatsu, Hirotoshi Sakaguchi, Ronald L. Paquette, Michael A. McDevitt, Seiji Kojima, Yogen Saunthararajah, Satoru Miyano, Lee-Yung Shih, Yang Du, Seishi Ogawa, Jaroslaw P. Maciejewski

NATURE GENETICS 45 ( 8 ) 942 - U298 2013年8月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Here we report whole-exome sequencing of individuals with various myeloid malignancies and identify recurrent somatic mutations in SETBP1, consistent with a recent report on atypical chronic myeloid leukemia (aCML)(1). Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS)(2), were detected in 17% of secondary acute myeloid leukemias (sAML) and 15% of chronic myelomonocytic leukemia (CMML) cases. These results from deep sequencing demonstrate a higher mutational detection rate than reported with conventional sequencing methodology(3-5). Mutant cases were associated with advanced age and monosomy 7/deletion 7q (-7/del(7q)) constituting poor prognostic factors. Analysis of serially collected samples indicated that SETBP1 mutations were acquired during leukemic evolution. Transduction with mutant Setbp1 led to the immortalization of mouse myeloid progenitors that showed enhanced proliferative capacity compared to cells transduced with wild-type Setbp1. Somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation and convey poor prognosis in myelodysplastic syndromes (MDS) and CMML.

DOI： 10.1038/ng.2696

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Integrated molecular analysis of clear-cell renal cell carcinoma 査読

Yusuke Sato, Tetsuichi Yoshizato, Yuichi Shiraishi, Shigekatsu Maekawa, Yusuke Okuno, Takumi Kamura, Teppei Shimamura, Aiko Sato-Otsubo, Genta Nagae, Hiromichi Suzuki, Yasunobu Nagata, Kenichi Yoshida, Ayana Kon, Yutaka Suzuki, Kenichi Chiba, Hiroko Tanaka, Atsushi Niida, Akihiro Fujimoto, Tatsuhiko Tsunoda, Teppei Morikawa, Daichi Maeda, Haruki Kume, Sumio Sugano, Masashi Fukayama, Hiroyuki Aburatani, Masashi Sanada, Satoru Miyano, Yukio Homma, Seishi Ogawa

NATURE GENETICS 45 ( 8 ) 860 - U191 2013年8月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood. Here we report an integrated molecular study of ccRCC in which >= 100 ccRCC cases were fully analyzed by whole-genome and/or whole-exome and RNA sequencing as well as by array-based gene expression, copy number and/or methylation analyses. We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on tumor behavior. Defective VHL-mediated proteolysis was a common feature of ccRCC, which was caused not only by VHL inactivation but also by new hotspot TCEB1 mutations, which abolished Elongin C-VHL binding, leading to HIF accumulation. Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT-mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing. This integrated molecular analysis unmasked new correlations between DNA methylation, gene mutation and/or gene expression and copy number profiles, enabling the stratification of clinical risks for patients with ccRCC.

DOI： 10.1038/ng.2699

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An empirical Bayesian framework for somatic mutation detection from cancer genome sequencing data 査読

Yuichi Shiraishi, Yusuke Sato, Kenichi Chiba, Yusuke Okuno, Yasunobu Nagata, Kenichi Yoshida, Norio Shiba, Yasuhide Hayashi, Haruki Kume, Yukio Homma, Masashi Sanada, Seishi Ogawa, Satoru Miyano

NUCLEIC ACIDS RESEARCH 41 ( 7 ) e89 2013年4月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OXFORD UNIV PRESS

Recent advances in high-throughput sequencing technologies have enabled a comprehensive dissection of the cancer genome clarifying a large number of somatic mutations in a wide variety of cancer types. A number of methods have been proposed for mutation calling based on a large amount of sequencing data, which is accomplished in most cases by statistically evaluating the difference in the observed allele frequencies of possible single nucleotide variants between tumours and paired normal samples. However, an accurate detection of mutations remains a challenge under low sequencing depths or tumour contents. To overcome this problem, we propose a novel method, Empirical Bayesian mutation Calling ( ext-link-type="uri" xlink:href="https://github.com/friend1ws/EBCall" xmlns:xlink="http://www.w3.org/1999/xlink">https://github.com/friend1ws/EBCall), for detecting somatic mutations. Unlike previous methods, the proposed method discriminates somatic mutations from sequencing errors based on an empirical Bayesian framework, where the model parameters are estimated using sequencing data from multiple non-paired normal samples. Using 13 whole-exome sequencing data with 87.5-206.3 mean sequencing depths, we demonstrate that our method not only outperforms several existing methods in the calling of mutations with moderate allele frequencies but also enables accurate calling of mutations with low allele frequencies (10%) harboured within a minor tumour subpopulation, thus allowing for the deciphering of fine substructures within a tumour specimen.

DOI： 10.1093/nar/gkt126

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全エクソンシークエンスによる淡明細胞型腎細胞癌の遺伝子変異解析(Comprehensive analysis of gene mutations in clear cell renal cell carcionoma)

佐藤悠佑, 前川滋克, 永田安伸, 吉田健一, 松原亜以子, 白石友一, 奥野友介, 鈴木啓道, 真田昌, 久米春喜, 宮野悟, 本間之夫, 小川誠司

日本癌学会総会記事 71回 545 - 545 2012年8月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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脳腫瘍の進展における遺伝子異常変化の解析(On the intratumoral heterogeneity underlying progression and/or chemoresistance of low-grade gliomas)

鈴木啓道, 夏目敦至, 佐藤悠佑, 吉田健一, 永田安伸, 奥野友介, 白石友一, 松原亜以子, 大岡史治, 真田昌, 宮野悟, 小川誠司, 若林俊彦

日本癌学会総会記事 71回 521 - 522 2012年8月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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全エクソーム解析による小児急性骨髄性白血病の新規発症原因遺伝子変異の同定(Identification of Somatic Mutations in pediatric Acute Myeloid Leukeimia Using Whole-Exome Sequencing)

柴徳生, 吉田健一, 奥野友介, 白石友一, 田中洋子, 永田安伸, 滝田順子, 荒川浩一, 伊藤悦朗, 真田昌, 宮野悟, 小川誠司, 林泰秀

日本癌学会総会記事 71回 475 - 475 2012年8月

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記述言語：英語出版者・発行元：日本癌学会

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SRSF2遺伝子変異の機能的解析(Functional analysis of SRSF2 mutation)

松縄学, 真田昌, 山本玲, 吉田健一, 永田安伸, 昆彩奈, 吉里哲一, 大津真, 中内啓光, 小川誠司

日本癌学会総会記事 71回 186 - 186 2012年8月

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記述言語：英語出版者・発行元：(一社)日本癌学会

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全エクソンシーケンス・全ゲノムシーケンスによって明らかになったMDSにおける遺伝子変異の全貌および腫瘍内の不均一性(Spectrum of gene mutations and intratumor heterogeneity in MDS revealed by whole-exome and whole genome sequencing)

吉田健一, 奥野友介, 白石友一, 昆彩奈, 永田安伸, 真田昌, 千葉健一, 田中洋子, 森啓, 石山謙, 千葉滋, 宮野悟, 小川誠司

日本癌学会総会記事 71回 445 - 446 2012年8月

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記述言語：英語出版者・発行元：日本癌学会

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Frequent pathway mutations of splicing machinery in myelodysplasia 査読

Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak, Yasunobu Nagata, Ryo Yamamoto, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masao Nagasaki, George Chalkidis, Yutaka Suzuki, Masashi Shiosaka, Ryoichiro Kawahata, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee-Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

NATURE 478 ( 7367 ) 64 - 69 2011年10月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (similar to 45 to similar to 85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved inhuman pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.

DOI： 10.1038/nature10496

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OP-091 腎細胞癌における網羅的ゲノム解析(腎腫瘍/基礎,一般演題口演,第99回日本泌尿器科学会総会)

佐藤悠佑, 松原亜以子, 永田安伸, 吉田健一, 川幡亮一郎, 真田昌, 久米春喜, 小川誠司, 本間之夫

日本泌尿器科学会雑誌 102 ( 2 ) 356 - 356 2011年

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記述言語：日本語出版者・発行元：一般社団法人日本泌尿器科学会

DOI： 10.5980/jpnjurol.102.356_1

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Acute Adverse Effects of Radiation Therapy on HIV-positive Patients in Japan: Study of 31 Cases at Tokyo Metropolitan Komagome Hospital 査読

Takuya Kaminuma, Katsuyuki Karasawa, Nahoko Hanyu, Ta-Chen Chang, Gencho Kuga, Naoko Okano, Nobuteru Kubo, Yusuke Okuma, Yasunobu Nagata, Yoshiharu Maeda, Atsushi Ajisawa

JOURNAL OF RADIATION RESEARCH 51 ( 6 ) 749 - 753 2010年11月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN RADIATION RESEARCH SOC

Recently, the number of human immunodeficiency virus (HIV) -positive patients has increased in Japan. HIV-positive patients are at a higher risk of cancer than the general population. This paper retrospectively reports the acute adverse effects of radiation therapy on HIV-positive patients who were treated at Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital (TMCICK). Thirty-one cases involving 24 HIV-positive cancer patients who were treated at TMCICK from January 1997 to March 2009 were included in this study. All acute adverse effects of radiation therapy were examined during, and one month after, the last radiation therapy session. Acute adverse effects were classified according to the site of radiation therapy treatment and analyzed using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 acute adverse effects were seen in 17% of cases, and Grade 2 toxicities were found in 23% of patients. Damage to the skin and mucosa, including stomatitis or diarrhea, tended to occur after low-dose radiation therapy; however, no severe acute adverse effects were seen in other organs, such as the brain, lung, and bone. Acute adverse effects tended to occur earlier in HIV-positive patients and became severe more frequently than in the general population. In particular, disorders of the mucosa, such as those of the oral cavity, pharynx, and intestine, tended to occur rapidly. It was shown that radiation therapy is safe when treatment is performed carefully and that it is a very useful treatment for cancer in HIV-positive patients.

DOI： 10.1269/jrr.10090

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骨髄異形成症候群の遺伝学的基盤(Genetic basis of myelodysplastic syndromes)

真田昌, 永田安伸, 吉田健一, 川幡亮一郎, 加藤元博, 松原亜以子, 石山謙, 石川隆之, 森啓, 宮脇修一, 小川誠司

日本癌学会総会記事 69回 228 - 228 2010年8月

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記述言語：英語出版者・発行元：日本癌学会

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MDSにおける全エクソン領域のシークエンス解析(Whole-exon sequencing of myelodysplastic syndromes)

永田安伸, 真田昌, 川幡亮一郎, 吉田健一, 加藤元博, 松原亜以子, 石山謙, 森啓, 宮脇修一, 石川隆之, 小川誠司

日本癌学会総会記事 69回 85 - 85 2010年8月

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記述言語：英語出版者・発行元：日本癌学会

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Clinical features of dasatinib-induced large granular lymphocytosis and pleural effusion 査読

Yasunobu Nagata, Kazuteru Ohashi, Shiomi Fukuda, Noriko Kamata, Hideki Akiyama, Hisashi Sakamaki

INTERNATIONAL JOURNAL OF HEMATOLOGY 91 ( 5 ) 799 - 807 2010年6月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

During follow-up of leukocyte counts in 20 consecutive patients (age range 29-81 years) treated with dasatinib, 9 patients (7 chronic myeloid leukemia in chronic phase, 2 Philadelphia chromosome-positive acute lymphoid leukemia in complete remission) developed lymphocytosis (> 3,000/mu l). Peripheral blood smears revealed a population of large granular lymphocytes. Large granular lymphocytosis (LGL) was first noted between 1 and 8 months after initiation of dasatinib, and it has persisted up to 33 months from the onset of LGL in one patient. Peak numbers of large granular lymphocytes ranged from 2,915 to 17,425/mu l. The occurrence of LGL might interfere with achieving molecular response (MR, real-time quantification of major BCR-ABL1 mRNA less than 50 copies/mu g RNA) in our small cohort; 8 (89%) of 9 patients with LGL attained MR, while only 6 (55%) of 11 patients without LGL eventually achieved MR. With respect to the relationship between LGL and pleural effusion (PE), 3 (27%) of 11 patients without LGL developed PE, while 5 (56%) of 9 patients with LGL developed PE. Moreover, the mean peak number of LGL was 9,215/mu l, which was much higher than the mean peak number (4,635/mu l) of LGL in patients without PE. These results may suggest possible association of both events in our cohorts.

DOI： 10.1007/s12185-010-0565-1

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Safe switching from dasatinib to nilotinib after a 1-month off-drug period for persistent pleural effusion in patients with chronic myelogenous leukemia in chronic phase 査読

Yasunobu Nagata, Shiomi Fukuda, Takeshi Kobayashi, Takuya Yamashita, Kazuteru Ohashi, Hisashi Sakamaki, Hideki Akiyama

INTERNATIONAL JOURNAL OF HEMATOLOGY 91 ( 3 ) 539 - 541 2010年4月

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記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

The approval of two new tyrosine kinase (TK) inhibitors, nilotinib and dasatinib, has raised the issue of cross-intolerance. Evaluating the safety of interchanging TK inhibitors is particularly important for patients who are intolerant to one medication but are considered to be sensitive to the other. Available data are limited and it is unclear whether switching between TK inhibitors is possible without an off-drug period. We present two patients with chronic myelogenous leukemia in whom, following the development of symptomatic pleural effusion, medications were safely switched from dasatinib to nilotinib after a 1-month off-drug period. The lymphocytosis and increased large granular lymphocyte count observed during dasatinib treatment also subsided after switching medications.

DOI： 10.1007/s12185-010-0526-8

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A case of colon cancer with reversible posterior leukoencephalopathy syndrome following 5-FU and oxaliplatin (FOLFOX Regime) 査読

Yasunobu Nagata, Yasushi Omuro, Tatsu Shimoyama, Eisaku Sasaki, Rumiko Okamoto, Yoshiharu Maeda, Shuji Kishida, Tsuneo Sasaki

Japanese Journal of Cancer and Chemotherapy 36 ( 7 ) 1163 - 1166 2009年

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記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

We report a rare case of reversible posterior leukoencephalopathy syndrome (RPLS) induced by 5-FU and oxaliplatin (FOLFOX regime). A 35-year-old woman with ileus was diagnosed with sigmoid cancer Stage IV (T4N4M0P2H0), and excision of the sigmoid colon, and left ureteroureteral anastomosis was performed. Postoperative chemotherapy with FOLFOX4 was performed. Complications of hypertension were seen on day 6, and convulsions on day 11 after chemotherapy. Headache and visual disturbance were also complications. MRI of the brain revealed bilateral high signal intensities of posterior lobes on T2 weighted and FLAIR images without enhancement. The patient was treated with antihypertensive therapy and anticonvulsive therapy. Her symptoms entirely disappeared, including the bilateral posterior lesions on MRI after two weeks. This report would suggest that medical oncologists should be aware that multidrug chemotherapies may increase the risk of fatal neurological complications like RPLS.

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▼全件表示

書籍等出版物

成熟型T細胞リンパ腫におけるRHOA変異の特徴

永田安伸（担当：分担執筆範囲: 血液フロンティア 27巻6号 (pp.854-859)）

医薬ジャーナル社 2017年5月

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遺伝子異常と病因（遺伝子異常やFLT3,NPM1 など病勢に関係している遺伝子異常の違い）

永田安伸（担当：分担執筆範囲: 急性白血病改訂第2 版 (pp44-56)）

最新医学社 2012年8月

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高齢者の急性骨髄性白血病に対する治療選択と予後について

永田安伸（担当：分担執筆範囲: 血液・腫瘍科 60/2）

科学評論社 2010年2月

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MISC

Sex-specific Differences In Risk Profiles For Cancer Among 19702 Japanese Patients With Ischemic Stroke: The Biobank Japan Project

Takashi Shimoyama, Koichi Matsuda, Yasunobu Nagata, Hiroki Yamaguchi, Kazumi Kimura

STROKE 54 2023年2月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

DOI： 10.1161/str.54.suppl_1.TP202

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Amplified EPOR/JAK2 genes definea unique subtype of acute erythroid leukemia.

June Takeda, Kenichi Yoshida, Masahiro M. Nakagawa, Yasuhito Nannya, Akinori Yoda, Ryunosuke Saiki, Yotaro Ochi, Lanying Zhao, Rurika Okuda, Xingxing Qi, Takuto Mori, Ayana Kon, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Ming-Chung Kuo, Cassandra Kerr, Yasunobu Nagata, Daisuke Morishita, Nobuhiro Hiramoto, Akira Hangaishi, Hideyuki Nakazawa, Ken Ishiyama, Satoru Miyano, Shigeru Chiba, Yasushi Miyazaki, Toshiyuki Kitano, Kensuke Usuki, Nobuo Sezaki, Hisashi Tsurumi, Shuichi Miyawaki, Jaroslaw P. Maciejewski, Takayuki Ishikawa, Kazuma Ohyashiki, Arnold Ganser, Michael Heuser, Felicitas Thol, Lee-Yung Shih, Akifumi Takaori-Kondo, Hideki Makishima, Seishi Ogawa

CANCER RESEARCH 82 ( 12 ) 2022年6月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

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EPOR/JAK/STAT経路は急性赤血球白血病における有望な治療標的である【JST・京大機械翻訳】|||

竹田淳恵, 吉田健一, 依田成玄, 南谷泰仁, SHIH Leeyung, 越智陽太郎, 白石友一, KERR Cassandra, 永田安伸, 北野俊行, 半下石明, 石山謙, 鶴見寿, 宮崎泰司, 平本展大, 石川隆之, 中川正宏, 高折晃史, 千葉滋, 中澤英之, KUO Mingchung, 片岡圭亮, 佐伯龍之介, 眞田昌, 臼杵憲祐, 宮脇修一, 宮野悟, MACIEJEWSKI Jaroslaw, 牧島秀樹, 小川誠司, 小川誠司, 小川誠司

日本血液学会学術集会抄録(Web) 83rd 2021年

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FLT3-ITD陽性AMLにおけるゲレリチニブによる特異な症候群の1例【JST・京大機械翻訳】|||

竹吉敦志, 丸毛淳史, 土蔵太一朗, 尾内大志, 阪口正洋, 由井俊輔, 永田安伸, 朝山敏夫, 脇田知志, 猪口孝一, 山口博樹

日本血液学会学術集会抄録(Web) 83rd 2021年

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Genotype-Phenotype Relationships and Therapeutic Targets in Acute Erythroid Leukemia

June Takeda, Kenichi Yoshida, Akinori Yoda, Lee-Yung Shih, Yasuhito Nannya, Yotaro Ochi, Ayana Kon, Kenichi Chiba, Yuichi Shiraishi, Yusuke Shiozawa, Tetsuichi Yoshizato, Cassandra M. Kerr, Yasunobu Nagata, Toshiyuki Kitano, Akira Hangaishi, Ken Ishiyama, Hisashi Tsurumi, Yasushi Miyazaki, Nobuhiro Hiramoto, Takayuki Ishikawa, Masahiro Marshall Nakagawa, Akifumi Takaori-Kondo, Shigeru Chiba, Hideyuki Nakazawa, Ming-Chung Kuo, Keisuke Kataoka, Ryunosuke Saiki, Hiroko Tanaka, Kensuke Usuki, Shuichi Miyawaki, Satoru Miyano, Jaroslaw P. Maciejewski, Arnold Ganser, Michael Heuser, Felicitas Thol, Hideki Makishima, Seishi Ogawa

BLOOD 136 2020年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

0

DOI： 10.1182/blood-2020-141750

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Clinical Impacts of Germline DDX41 Mutations on Myeloid Neoplasms

Hideki Makishima, Yasuhito Nannya, June Takeda, Yukihide Momozawa, Ryunosuke Saiki, Tetsuichi Yoshizato, Yoshiko Atsuta, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Yusuke Shiozawa, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Nobuyuki Kakiuchi, Yotaro Ochi, Hiroo Ueno, Hidehiro Itonaga, Yoshinobu Kanda, Masashi Sanada, Ayana Kon, Yasushi Miyazaki, Keizo Horibe, Magnus Tobiasson, Hisashi Tsurumi, Senji Kasahara, Chantana Polprasert, Eva Hellstrom Lindberg, Akifumi Kondo Takaori, Toru Kiguchi, Mario Cazzola, Fumihiko Matsuda, Kazuma Ohyashiki, Jaroslaw P. Maciejewski, Torsten Haferlach, Yoichiro Kamatani, Michiaki Kubo, Satoru Miyano, Seishi Ogawa

BLOOD 136 2020年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

0

DOI： 10.1182/blood-2020-140174

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急性赤白血病に対するJAK-STATパスウェイ阻害薬の有用性の検討

竹田淳恵, 吉田健一, 依田成玄, 南谷泰仁, SHIH Leeyung, 越智陽太郎, 白石友一, KERR Cassandra, 永田安伸, 北野俊行, 半下石明, 石山謙, 鶴見寿, 宮崎泰司, 平本展大, 石川隆之, 中川正宏, 高折晃史, 千葉滋, 中澤英之, KUO Mingchung, 片岡圭亮, 佐伯龍之介, 真田昌, 臼杵憲祐, 宮脇修一, 宮脇修一, 宮野悟, MACIEJEWSKI Jaroslaw, MACIEJEWSKI Jaroslaw, 牧島秀樹, 小川誠司, 小川誠司, 小川誠司

日本血液学会学術集会抄録(Web) 82nd 2020年

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J-GLOBAL

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Der(1;7) 陽性骨髄異形成症候群における人種,臨床像,遺伝学的観点からみた特徴

奥田瑠璃花, 南谷泰仁, 越智陽太郎, 蝶名林和久, 蝶名林和久, 牧島秀樹, 吉里哲一, 永田安伸, 竹田淳恵, 吉田健一, 真田昌, 真田昌, 昆彩奈, 白石友一, 宮野悟, 宮野悟, KERN Wolfgang, BAER Constance, NADARAJAH Niroshan, ALPERMANN Tamara, HAFERLACH Claudia, 熱田由子, 笠原千嗣, 半田寛, 千葉滋, 大屋敷一馬, HAFERLACH Torsten, 吉田善紀, 小川誠司, 小川誠司, 小川誠司

日本血液学会学術集会抄録(Web) 82nd 2020年

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Novel Molecular Pathogenesis and Therapeutic Target in Acute Erythroid Leukemia

June Takeda, Kenichi Yoshida, Yasuhito Nannya, Lee-Yung Shih, Ayana Kon, Akinori Yoda, Yotaro Ochi, Yusuke Shiozawa, Tetsuichi Yoshizato, Cassandra M. Kerr, Yuichi Shiraishi, Kenichi Chiba, Yasunobu Nagata, Akira Hangaishi, Toshiyuki Kitano, Ken Ishiyama, Hisashi Tsurumi, Yasushi Miyazaki, Nobuhiro Hiramoto, Takayuki Ishikawa, Akifumi Takaori-Kondo, Masahiro Nakagawa, Masashi Sanada, Hideyuki Nakazawa, Keisuke Kataoka, Ryunosuke Saiki, Hiroko Tanaka, Kensuke Usuki, Shuichi Miyawaki, Satoru Miyano, Arnold Ganser, Michael Heuser, Jaroslaw P. Maciejewski, Felicitas Thol, Hideki Makishima, Seishi Ogawa

BLOOD 134 2019年11月

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0

DOI： 10.1182/blood-2019-129940

Web of Science

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DNA Methylation and Genetic Profiles in 320 Patients with Myelodysplastic Syndromes

Suguru Morimoto, Hideki Makishima, Yasunobu Nagata, Niroshan Nadarajah, Constance Baer, Tamara Alpermann, Genta Nagae, Yasuhito Nannya, Yasushi Miyazaki, Kenichi Yoshida, Tetsuichi Yoshizato, Masahiro Marshall Nakagawa, Ryosaku Inagaki, June Takeda, Yoichi Fujii, Yasuhide Takeuchi, Hiroo Ueno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Satoru Miyano, Claudia Haferlach, Wolfgang Kern, Hiroyuki Aburatani, Torsten Haferlach, Seishi Ogawa

BLOOD 132 2018年11月

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0

DOI： 10.1182/blood-2018-99-116489

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骨髄異形成症候群におけるder(1;7)に伴う遺伝子異常の意義(Distinct ethnic, genetic and phenotypic characteristics of der(1;7) in myelodysplastic syndromes)

奥田瑠璃花, 牧島秀樹, 吉里哲一, 南谷泰仁, 永田安伸, 竹田淳恵, 吉田健一, 眞田昌, 白石友一, 宮野悟, Kern Wolfgang, Baer Constance R, Nadarajah Niroshan, Alpermann Tamara, Haferlach Claudia, 笠原千嗣, 半田寛, 千葉滋, Haferlach Torsten, 小川誠司

臨床血液 59 ( 9 ) 1588 - 1588 2018年9月

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記述言語：英語出版者・発行元：(一社)日本血液学会-東京事務局

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Neuroendoscopic Cylinder Surgery and 5-Aminolevulinic Acid Photodynamic Diagnosis of Deep-Seated Intracranial Lesions.

Choo J, Takeuchi K, Nagata Y, Ohka F, Kishida Y, Watanabe T, Satoh Y, Nagatani T, Kato K, Wakabayashi T, Natsume A

World neurosurgery 116 e35 - e41 2018年3月

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記述言語：英語掲載種別：速報，短報，研究ノート等（学術雑誌）

DOI： 10.1016/j.wneu.2018.03.112

Scopus

PubMed

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GENETIC LANDSCAPE OF ACUTE ERYTHROID LEUKEMIA

J. Takeda, L. -Y. Shih, K. Chiba, Y. Shiraishi, Y. Shiozawa, H. Makishima, T. Yoshizato, Y. Nagata, A. Hangaishi, K. Ishiyama, A. Takaori-Kondo, K. Kataoka, M. Sanada, H. Tanaka, K. Usuki, S. Miyawaki, S. Miyano, A. Ganser, M. Heuser, S. Ogawa, F. Thol, K. Yoshida

HAEMATOLOGICA 102 205 - 206 2017年6月

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Web of Science

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ANCESTRAL EVENTS INCLUDING GERMLINE AND SOMATIC MUTATIONS DETERMINE SUBCLONAL EVENTS AND AFFECT PHENOTYPE OF PROGRESSION IN MDS

Y. Nagata, H. Makishima, T. Radivoyevitch, C. Hirsch, B. Przychodzen, T. Kuzmanovic, S. Li, K. Yoshida, H. Suzuki, V. Adema, M. Clemente, Y. Shiraishi, K. Chiba, H. Tanaka, F. Sole, S. Miyano, M. Sekeres, T. LaFramboise, S. Ogawa, J. Maciejewski

LEUKEMIA RESEARCH 55 S8 - S8 2017年4月

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Web of Science

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Clinical and Biological Implications of CUX1 Mutations in Myeloid Neoplasms

Mai Aly, Naoko Hosono, Przychodzen Bartlomiej, Hideki Makishima, Nagata Yasunobu, Cassandra M. Hirsch, Mikkael A. Sekeres, Jaroslaw P. Maciejewski

BLOOD 128 ( 22 ) 2016年12月

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Landscape of Subclonal Mutations in Myelodysplastic Syndromes (MDS) Allows for a Novel Hierarchy of Clonal Advantage By Combining Germline and Somatic Mutations

Yasunobu Nagata, Hideki Makishima, Tomas Radivoyevitch, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, Teodora Kuzmanovic, Samuel Li, Kenichi Yoshida, Tetsuichi Yoshizato, Vera Adema, Eiju Negoro, Michael J. Clemente, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Sudipto Mukherjee, Aziz Nazha, Francesc Sole, Hetty E. Carraway, Satoru Miyano, Thomas LaFramboise, Mikkael A. Sekeres, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 128 ( 22 ) 2016年12月

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Web of Science

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Clonal Events of Aplastic Anemia Related to the Evolution to Myelodysplastic Syndrome

Eiju Negoro, Michael Clemente, Naoko Hosono, Aziz Nazha, Wenyi Shen, Yasunobu Nagata, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, Reda Z. Mahfouz, Teodora Kuzmanovic, Hideki Makishima, Mikkael A. Sekeres, Jaroslaw P. Maciejewski

BLOOD 128 ( 22 ) 2016年12月

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Web of Science

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Integrated Molecular Analysis of Myelodysplastic Syndromes Using Whole Genome Sequencing

Yasuito Nannya, Yoshida Kenichi, Keisuke Kataoka, Yasunobu Nagata, Tetsuichi Yoshizato, Tomoki Naoe, Hitoshi Kiyoi, Shigeru Chiba, Norio Asou, Yasushi Miyazaki, Hiroko Tanaka, Kenichi Chiba, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa

BLOOD 128 ( 22 ) 2016年12月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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UTX mutations in Myeloid Neoplasms

Yasunobu Nagata, Tomas Radivoyevitch, Hideki Makishima, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, Teodora Kuzmanovic, Eiju Negoro, Michael J. Clemente, Sudipto Mukherjee, Hetty E. Carraway, Mikkael A. Sekeres, Jaroslaw P. Maciejewski

BLOOD 128 ( 22 ) 2016年12月

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Web of Science

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Genetic Profile of Acute Erythroid Leukemia

June Takeda, Kenichi Chiba, Yuichi Shiraishi, Tetsuichi Yoshizato, Yusuke Shiozawa, Yasunobu Nagata, Akira Hangaishi, Ken Ishiyama, Keisuke Kataoka, Masashi Sanada, Hiroko Tanaka, Kensuke Usuki, Shuichi Miyawaki, Satoru Miyano, Arnold Ganser, Seishi Ogawa, Michael Heuser, Felicitas Thol, Kenichi Yoshida

BLOOD 128 ( 22 ) 2016年12月

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Web of Science

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the Impact of Clonal Dynamics on Prognosis and Outcome in Myelodysplastic Syndromes

Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, Mikkael A. Sekeres, Tomas Radivoyevitch, Hiromichi Suzuki, Bartlomiej P. Przychodzen, Yasunobu Nagata, Manja Meggendorfer, Masashi Sanada, Yusuke Okuno, Cassandra M. Hirsch, Teodora Kuzmanovic, Yusuke Shiozawa, Yusuke Sato, Aiko Sato-Otsubo, Thomas LaFramboise, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Claudia Haferlach, Wolfgang Kern, Hiroko Tanaka, Ines Gomez-Segui, Holleh Husseinzadeh, Swapna Thota, Kathryn M. Guinta, Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Torsten Haferlach, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 128 ( 22 ) 2016年12月

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低悪性度神経膠腫の予後に関与する遺伝子異常の解析

青木恒介, 鈴木啓道, 松尾恵太郎, 片岡圭亮, 島村徹平, 永田安伸, 吉里哲一, 真田昌, 宮野悟, 若林俊彦, 小川誠司, 夏目敦至

日本癌学会総会記事 75回 E - 1013 2016年10月

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記述言語：英語出版者・発行元：日本癌学会

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成人T細胞性白血病/リンパ腫における全遺伝子プロファイリングと予後の相関

越智陽太郎, 片岡圭亮, 永田安伸, 北中明, 安永純一朗, 岩永正子, 白石友一, 千葉健一, 佐藤亜衣子, 真田昌, 田中洋子, 鈴木啓道, 佐藤悠佑, 塩澤裕介, 吉里哲一, 吉田健一, 野坂生郷, 菱澤方勝, 今泉芳孝, 日高智徳, 中牧剛, 宮脇修一, 飛内賢正, 宮崎泰司, 高折晃史, 柴田龍弘, 宮野悟, 下田和哉, 松岡雅雄, 渡邉俊樹, 小川誠司

日本癌学会総会記事 75回 J - 1029 2016年10月

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記述言語：英語出版者・発行元：日本癌学会

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PROGNOSTIC IMPACT OF INTEGRATED GENOMIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA

K. Kataoka, Y. Nagata, A. Kitanaka, J. I. Yasunaga, M. Iwanaga, Y. Shiraishi, K. Chiba, A. Sato-Otsubo, M. Sanada, H. Tanaka, H. Suzuki, Y. Sato, Y. Shiozawa, T. Yoshizato, K. Yoshida, K. Nosaka, M. Hishizawa, H. Itonaga, Y. Imaizumi, W. Munakata, K. Shide, Y. Kubuki, T. Hidaka, T. Kameda, T. Nakamaki, K. Ishiyama, S. Miyawaki, K. Tobinai, Y. Miyazaki, A. Takaori-Kondo, T. Shibata, S. Miyano, M. Matsuoka, K. Shimoda, T. Watanabe, S. Ogawa

HAEMATOLOGICA 101 269 - 269 2016年6月

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Web of Science

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DYNAMICS OF CLONAL EVOLUTION IN MYELODYSPLASTIC SYNDROMES

H. Makishima, T. Yoshizato, K. Yoshida, T. LaFramboise, M. Ruffalo, M. Sekeres, H. Suzuki, B. Przychodzen, Y. Nagata, M. Meggendorfer, M. Sanada, Y. Okuno, Y. Sato, A. Sato-Otsubo, T. Radivoyevitch, N. Hosono, Y. Shiraishi, K. Chiba, C. Haferlach, W. Kern, H. Tanaka, Y. Shiozawa, I. Gomez-Segui, H. Husseinzadeh, S. Thota, K. Guinta, B. Dienes, T. Nakamaki, S. Miyawaki, Y. Saunthararajah, S. Chiba, S. Miyano, Ly Shih, T. Haferlach, S. Ogawa, J. Maciejewski

HAEMATOLOGICA 101 157 - 157 2016年6月

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Web of Science

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GENETIC FACTORS ASSOCIATED WITH EVOLUTION OF MYELODYSPLASTIC SYNDROMES TO SECONDARY CHRONIC MYELOMONOCYTIC LEUKEMIA

R. Saiki, T. Yoshizato, B. Przychodzen, K. Yoshida, M. A. Sekeres, Y. Nagata, M. Meggendorfer, M. Sanada, Y. Okuno, A. Kon, H. Suzuki, Y. Sato, Y. Shiraishi, K. Chiba, C. Haferlach, W. Kern, H. Tanaka, Y. Shiozawa, K. M. Guinta, T. Nakamaki, S. Miyawaki, Y. Saunthararajah, S. Chiba, S. Miyano, L. Y. Shih, A. F. List, S. Ogawa, T. Haferlach, J. P. Maciejewski, H. Makishima

HAEMATOLOGICA 101 493 - 494 2016年6月

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Array CGH identifies copy number changes in 11% of 520 MDS patients with normal karyotype and uncovers prognostically relevant deletions

S. Volkert, T. Haferlach, J. Holzwarth, M. Zenger, W. Kern, M. Staller, Y. Nagata, K. Yoshida, S. Ogawa, S. Schnittger, C. Haferlach

LEUKEMIA 30 ( 1 ) 257 - 260 2016年1月

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記述言語：英語掲載種別：速報，短報，研究ノート等（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

DOI： 10.1038/leu.2015.257

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ATLにおける網羅的遺伝子プロファイルが予後に与える影響の解析

越智陽太郎, 片岡圭亮, 永田安伸, 北中明, 安永純一朗, 岩永正子, 野坂生郷, 糸永英弘, 今泉芳孝, 幣光太郎, 宮崎泰司, 高折晃史, 下田和哉, 松岡雅雄, 渡邉俊樹, 小川誠司

日本HTLV‐1学会学術集会 3rd 57 2016年

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記述言語：日本語

J-GLOBAL

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Prognostic Relevance of Integrated Genetic Profiling in Adult T-Cell Leukemia/Lymphoma

Keisuke Kataoka, Yasunobu Nagata, Akira Kitanaka, Jun-ichirou Yasunaga, Masako Iwanaga, Yuichi Shiraishi, Kenichi Chiba, Aiko Sato-Otsubo, Masashi Sanada, Hiroko Tanaka, Hiromichi Suzuki, Yusuke Sato, Yusuke Shiozavva, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Kisato Nosaka, Masakatsu Hishizawa, Hidehiro Itonaga, Yoshitaka Imaizumi, Wataru Munakata, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Takuro Kameda, Tsuyoshi Nakamaki, Ken Ishiyama, Shuichi Miyawaki, Kensei Tobinai, Yasushi Miyazaki, Akifumi Takaori-Kondo, Tatsuhiro Shibata, Satoru Miyano, Masao Matsuoka, Kazuya Shimoda, Toshiki Watanabe, Seishi Ogawa

BLOOD 126 ( 23 ) 2015年12月

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Myelodysplastic Syndrome Patients Show Mutation-Specific DNA Methylation Patterns

Constance Regina Baer, Niroshan Nadarajah, Yasunobu Nagata, Tamara Alpermann, Genta Nagae, Yusuke Okuno, Yuichi Shiraishi, Satoru Miyano, Claudia Haferlach, Wolfgang Kern, Hiroyuki Aburatani, Seishi Ogawa, Torsten Haferlach

BLOOD 126 ( 23 ) 2015年12月

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Impact of Somatic Mutations on Outcome in Patients with MDS after Stem-Cell Transplantation

Tetsuichi Yoshizato, Yusuke Shiozawa, Kenichi Yoshida, Yoshiko Atsuta, Chika Ito, Keisuke Kataoka, Makoto Onizuka, Hiromichi Suzuki, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Yasunobu Nagata, Masashi Sanada, Hidehiro Itonaga, Yoshinobu Kanda, Yasushi Miyazaki, Hideki Makishima, Satoru Miyano, Seishi Ogawa

BLOOD 126 ( 23 ) 2015年12月

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Web of Science

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Genetic Predispositions to Myeloid Neoplasms Caused By Germline DDX41 Mutations

June Takeda, Kenichi Yoshida, Hideki Makishima, Tetsuichi Yoshizato, Yusuke Shiozama, Yuichi Shiraishi, Yusuke Okuno, Ayana Kon, Yasunobu Nagata, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Mamiko Sakata-Yanagimoto, Naoshi Obara, Tsuyoshi Nakamaki, Ken Ishiyama, Akira Haigaishi, Shigeru Chiba, Hiraku Mori, Norio Asou, Hitoshi Kiyoi, Chikara Hirase, Kiyotoshi Imai, Nobuaki Dobashi, Toru Kiguchi, Yasushi Miyazaki, Tomoki Naoe, Satoru Miyano, Kensuke Usuki, Shuichi Miyawaki, Yoichiro Kamatani, Yukihide Momozawa, Michiaki Kubo, Chantana Polprasert, Jaroslaw P. Maciejewski, Seishi Ogawa

BLOOD 126 ( 23 ) 2015年12月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Serial Sequencing in Myelodysplastic Syndromes Reveals Dynamic Changes in Clonal Architecture and Allows for a New Prognostic Assessment of Mutations Detected in Cross-Sectional Testing

Hideki Makishima, Kenichi Yoshida, Thomas LaFramboise, Tetsuichi Yoshizato, Matthew Ruffalo, Mikkael A. Sekeres, Bartlomiej Przychodzen, Hiromichi Suzuki, Masashi Sanada, Yasunobu Nagata, Yusuke Okuno, Yusuke Sato, Aiko Sato-Otsubo, Michael J. Clemente, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Yusuke Shiozawa, Ines Gomez-Segui, Holleh Husseinzadeh, Swapna Thota, Kathryn Guinta, Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 126 ( 23 ) 2015年12月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Two Novel Distinct Subtypes of Myeloid Neoplasms Molecularly Associated with Histone H3K36 Methylations

Yosaku Watatani, Yasunobu Nagata, Vera Grossmann, Yusuke Okuno, Tetsuichi Yoshizato, Yusuke Shiozawa, Genta Nagae, Kenichi Yoshida, Keisuke Kataoka, Susanne Schnittger, Masashi Sanada, Ayana Kon, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Tsuyoshi Nakamaki, Shuichi Miyawaki, Shigeru Chiba, Tamara Alpermann, Niroshan Nadarajah, Phillip Koeffler, Hans-Ulrich Klein, Martin Dugas, Hiroyuki Aburatani, Claudia Haferlach, Wolfgang Kern, Satoru Miyano, Lee-Yung Shih, Seishi Ogawa, Torsten Haferlach, Hideki Makishima

BLOOD 126 ( 23 ) 2015年12月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Integrative study of genomic alterations in liposarcoma

Deepika Kanojia, Manoj Garg, Yasunobu Nagata, Dhong Hyun Lee, Hans-Ulrich Klein, Christoph Bartenhagen, M. T. Anand, Ngan B. Doan, Jonathan W. Said, Henry Yang, Charles Forscher, Martin Dugas, Seishi Ogawa, H. Phillip Koeffler

CANCER RESEARCH 75 ( 22 ) 2015年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.TRANSCAGEN-A2-20

Web of Science

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造血器腫瘍における分子病態の理解と臨床応用への展望成人T細胞白血病リンパ腫におけるメチル化異常

片岡圭亮, 島村徹平, 北中明, 永江玄太, 永田安伸, 安永純一朗, 眞田昌, 白石友一, 宮野悟, 松岡雅雄, 油谷浩幸, 下田和哉, 小川誠司

日本癌学会総会記事 74回 SST5 - 5 2015年10月

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記述言語：英語出版者・発行元：日本癌学会

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BIOLOGICAL AND GENETIC CHARACTERIZATION OF THE ROLE OF SRSF2 MUTATIONS IN THE PATHOGENESIS OF MYELODYSPLASTIC SYNDROMES

Ayana Kon, Satoshi Yamazaki, Keisuke Kataoka, Tetsuichi Yoshizato, Yusuke Shiozawa, Masashi Sanada, Kenichi Yoshida, Yasunobu Nagata, Yuichi Shiraishi, Satoru Miyano, Torsten Haferlach, Manabu Nakayama, Haruhiko Koseki, Hiromitsu Nakauchi, Seishi Ogawa

EXPERIMENTAL HEMATOLOGY 43 ( 9 ) S73 - S73 2015年9月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：ELSEVIER SCIENCE INC

Web of Science

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The genomic landscape of nasopharyngeal carcinoma

Dechen Lin, Xuan Meng, Masaharu Hazawa, Yasunobu Nagata, Ana Maria Varela, Liang Xu, Yusuke Sato, Li-Zhen Liu, Ling-Wen Ding, Arjun Sharma, Boon Cher Goh, Soo Chin Lee, Bengt Fredrik Petersson, Feng Gang Yu, Paul Macary, Min Zin Oo, Soh Ha Chan, Henry Yang, Seishi Ogawa, H. Phillip Koeffler

CANCER RESEARCH 75 2015年8月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

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THE LANDSCAPE OF SOMATIC ALTERATIONS IN ADULT T-CELL LEUKEMIA/LYMPHOMA

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HAEMATOLOGICA 100 166 - 166 2015年6月

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FOUNDER AND SUBCLONAL SOMATIC MUTATIONS CONTRIBUTING TO LEUKEMIC EVOLUTION IN MYELODYSPLASTIC SYNDROMES AND RELATED MYELOID NEOPLASMS

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LEUKEMIA RESEARCH 39 S135 - S136 2015年4月

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ATLにおけるウイルスならびにホストのゲノムの統合的分子解析

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日本HTLV‐1学会学術集会 2nd 20 2015年

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J-GLOBAL

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In Analogy to AML, MDS Can be Sub-Classified By Ancestral Mutations

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BLOOD 124 ( 21 ) 2014年12月

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Chronological Analysis of Clonal Evolution in Acquired Aplastic Anemia

Tetsuichi Yoshizato, Bogdan Dumitriu, Kohei Hosokawa, Hideki Makishima, Kenichi Yoshida, Aiko Sato, Yusuke Okuno, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Yasunobu Nagata, Hiromichi Suzuki, Yusuke Sato, Yusuke Shiozawa, Takamasa Katagiri, Ayana Kon, Michael Clemente, Masashi Sanada, Satoru Miyano, Jaroslaw P. Maciejewski, Shinji Nakao, Neal S. Young, Seishi Ogawa

BLOOD 124 ( 21 ) 2014年12月

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Whole exome sequencing reveals the landscape of gene mutations and evolution in low-grade glioma

Hiromichi Suzuki, Atsushi Natsume, Yusuke Sato, Yuichi Shiraishi, Yusuke Shiozawa, Kenichi Yoshida, Yasunobu Nagata, Aiko Sato, Kazuya Motomura, Masazumi Fujii, Masashi Sanada, Satoru Miyano, Toshihiko Wakabayashi, Seishi Ogawa

CANCER RESEARCH 74 ( 19 ) 2014年10月

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Comprehensive molecular characterization of esophageal squamous cell carcinoma

Dechen Lin, Xuan Meng, Liang Xu, Lingwen Ding, Manoj Garg, Henry Yang, Lizhen Liu, Jiajie Hao, Mingrong Wang, Yasunobu Nagata, Yusuke Sato, Yusuke Okuno, Seishi Ogawa, Phillip Koeffler

CANCER RESEARCH 74 ( 19 ) 2014年10月

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EXOME SEQUENCING AND SNP ARRAY REVEAL EPIGENOME MODIFIER DEFECTS IN NASOPHARYNGEAL CARCINOMA

Xuan Meng, De-chen Lin, Yasunobu Nagata, Yasuke Sato, Boon Cher Goh, Soo Chin Lee, Feng Gang Yu, Seishi Ogawa, Kwok Seng Loh, H. Phillip Koeffler

ANNALS OF ONCOLOGY 25 2014年10月

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DOI： 10.1093/annonc/mdu435.42

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Genome-wide analysis of copy number alterations and gene mutations in testicular germ cell cancer

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CANCER RESEARCH 74 ( 19 ) 2014年10月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

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低悪性度神経膠腫における全エクソーム解析(Whole exome sequencing reveals the landscape of gene mutations and evolution in low-grade gliomas)

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日本癌学会総会記事 73回 E - 2056 2014年9月

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ATL発がん機構と治療の新展開成人T細胞白血病/リンパ腫におけるゲノム異常の網羅的解析(New insights on leukemogenesis of ATL and development of therapy Comprehensive genomic characterization of adult T-cell leukemia/lymphoma)

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日本癌学会総会記事 73回 S16 - 4 2014年9月

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記述言語：英語出版者・発行元：日本癌学会

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SF3B1 PLAYS AN IMPORTANT ROLE IN THE REGULATION OF HEMATOPOIETIC STEMS CELLS, BUT HAPLOINSUFFICIENCY OF SF3B1 MAY NOT BE SOLELY RESPONSIBLE FOR MYELODYSPLASIA

M. Matsunawa, R. Yamamoto, M. Sanada, A. Kon, A. Sato-Otsubo, Y. Shiozawa, K. Yoshida, Y. Nagata, T. Yoshizato, M. Otsu, K. Isono, H. Koseki, H. Nakauchi, S. Ogawa

HAEMATOLOGICA 99 234 - 235 2014年6月

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MOLECULAR PROFILING OF 944 PATIENTS WITH MYELODYSPLASTIC SYNDROMES USING DEEP SEQUENCING

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HAEMATOLOGICA 99 235 - 235 2014年6月

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CHRONOLOGICAL ANALYSIS OF CLONAL EVOLUTION IN ACQUIRED APLASTIC ANEMIA

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HAEMATOLOGICA 99 261 - 261 2014年6月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：FERRATA STORTI FOUNDATION

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WHOLE EXOME SEQUENCING REVEALS CLONAL EVOLUTION PATTERNS AND DRIVER GENETIC ALTERATIONS OF RELAPSED PEDIATRIC ACUTE MYELOID LEUKEMIA

K. Yoshida, N. Shiba, A. Shimada, K. Terui, M. Kato, Y. Shiraishi, Y. Okuno, Y. Nagata, A. Kon, K. Kataoka, T. Yoshizato, Y. Shiozawa, M. Matsunawa, K. Chiba, H. Tanaka, M. Sanada, S. Miyano, E. Ito, Y. Hayashi, S. Ogawa

HAEMATOLOGICA 99 16 - 17 2014年6月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：FERRATA STORTI FOUNDATION

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The landscape of somatic mutations in Down syndrome-related myeloid disorders (vol 45, pg 1293, 2013)

Kenichi Yoshida, Tsutomu Toki, Yusuke Okuno, Rika Kanezaki, Yuichi Shiraishi, Aiko Sato-Otsubo, Masashi Sanada, Myoung-ja Park, Kiminori Terui, Hiromichi Suzuki, Ayana Kon, Yasunobu Nagata, Yusuke Sato, RuNan Wang, Norio Shiba, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Hideki Muramatsu, Daisuke Hasegawa, Kazuhiro Nakamura, Hirokazu Kanegane, Keiko Tsukamoto, Souichi Adachi, Kiyoshi Kawakami, Koji Kato, Ryosei Nishimura, Shai Izraeli, Yasuhide Hayashi, Satoru Miyano, Seiji Kojima, Etsuro Ito, Seishi Ogawa

NATURE GENETICS 45 ( 12 ) 1516 - 1516 2013年12月

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記述言語：英語出版者・発行元：NATURE PUBLISHING GROUP

DOI： 10.1038/ng1213-1516

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Clinical "MUTATOME" Of Myelodysplastic Syndrome; Comparison To Primary Acute Myelogenous Leukemia

Hideki Makishima, Thomas LaFramboise, Bartlomiej P. Przychodzen, Kenichi Yoshida, Matthew Ruffalo, Ines Gomez-Segui, Holleh D. Husseinzadeh, Yuichi Shiraishi, Masashi Sanada, Yasunobu Nagata, Yusuke Sato, Aiko Sato-Otsubo, Kenichi Chiba, Hiroko Tanaka, Tsuyoshi Nakamaki, Wolf-Karsten Hofmann, Shuichi Miyawaki, Lee-Yung Shih, Shigeru Chiba, Satoru Miyano, Naoko Hosono, Chantana Polprasert, Swapna Thota, Brittney Dienes, Kathryn M. Guinta, Yogen Sauntharatajah, Mikkael A. Sekeres, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 122 ( 21 ) 2013年11月

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Landscape Of Genetic Lesions In 944 Patients With Myelodysplastic Syndromes

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BLOOD 122 ( 21 ) 2013年11月

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Spectrum Of Genetic Alterations In Acquired Aplastic Anemia

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BLOOD 122 ( 21 ) 2013年11月

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Whole Exome Analysis Of Germline Alterations Associated With Myelodysplastic Syndrome

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BLOOD 122 ( 21 ) 2013年11月

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Molecular Characterization Of Adult T-Cell Leukemia/Lymphoma

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BLOOD 122 ( 21 ) 2013年11月

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Role Of Sf3b1 On Hematopoiesis

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BLOOD 122 ( 21 ) 2013年11月

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IDENTIFICATION OF NOVEL SOMATIC MUTATIONS IN PEDIATRIC ACUTE MYELOID LEUKEIMIA USING WHOLE-EXOME RESEQUENCING

N. Shiba, K. Yoshida, Y. Okuno, Y. Shiraishi, A. Kon, Y. Nagata, K. Ohki, M. Park, M. Kato, T. Kanazawa, J. Takita, K. Kudo, H. Arakawa, E. Ito, M. Sanada, S. Miyano, S. Ogawa, Y. Hayashi

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BCOR and BCORL1 mutations in myelodysplasia: Prevalence, prognosis and clonal hierarchy

F. Damm, V. Chesnais, Y. Nagata, K. Yoshida, Y. Okuno, D. Birnbaum, S. Ogawa, O. A. Bernard, M. Fontenay, O. Kosmider

LEUKEMIA RESEARCH 37 S11 - S12 2013年5月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

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Genetic basis of myeloid leukemogenesis in Down syndrome

Kenichi Yoshida, Tsutomu Toki, Myoung-ja Park, Yusuke Okuno, Yuichi Shiraishi, Masashi Sanada, Ayana Kon, Yasunobu Nagata, Aiko Sato-Otsubo, Yusuke Sato, RuNan Wang, Kiminori Terui, Rika Kanezaki, Norio Shiba, Kenichi Chiba, Hiroko Tanaka, Asahito Hama, Daisuke Hasegawa, Kazuhiro Nakamura, Hirokazu Kanegane, Keiko Tsukamoto, Souichi Adachi, Satoru Miyano, Seiji Kojima, Shai Izraeli, Yasuhide Hayashi, Etsuro Ito, Seishi Ogawa

CANCER RESEARCH 73 ( 8 ) 2013年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

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Recurrent pathway mutations of multiple components of cohesin complex in myeloid neoplasms

Ayana Kon, Lee Yung Shih, Masashi Minamino, Masashi Sanada, Yuichi Shiraishi, Yasunobu Nagata, Kenichi Yoshida, Yusuke Okuno, Masashige Bando, Shunpei Ishikawa, Aiko Sato-Otsubo, Genta Nagae, Aiko Nishimoto, Claudia Haferiach, Daniel Nowak, Yusuke Sato, Tamara Alpermann, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Ryo Yamamoto, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Tsuyoshi Nakamaki, Ken Ishiyama, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Shigeru Chiba, Hiraku Mori, Hiromitso Nakauchi, H. Phillip Koeffler, Hiroyuki Aburatani, Torsten Haferlach, Katsuhiko Shirahige, Satoru Miyano, Seishi Ogawa

CANCER RESEARCH 73 ( 8 ) 2013年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

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Somatic Mutations in Schinzel-Giedion Syndrome Gene SETBP1 Determine Progression in Myeloid Malignancies

Hideki Makishima, Kenichi Yoshida, Nhu Nguyen, Masashi Sanada, Yusuke Okuno, Kwok Peng Ng, Bartlomiej P. Przychodzen, Kristbjorn O. Gudmundsson, Bandana A. Vishwakarma, Andres Jerez, Ines Gomez-Segui, Mariko Takahashi, Yuichi Shiraishi, Yasunobu Nagata, Kathryn M. Guinta, Hiraku Mori, Mikkael A. Sekeres, Kenichi Chiba, Hideki Muramatsu, Hirotoshi Sakaguchi, Ronald Paquette, Michael A. McDevitt, Seiji Kojima, Yogen Saunthararajah, Satoru Miyano, Lee-Yung Shih, Yang Du, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 120 ( 21 ) 2012年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

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Whole Exome Sequencing Reveals Spectrum of Gene Mutations in Pediatric AML

Norio Shiba, Kenichi Yoshida, Yusuke Okuno, Yuichi Shiraishi, Yasunobu Nagata, Kentarou Ohki, Motohiro Kato, Myoung-ja Park, Junko Takita, Takashi Kanazawa, Kazuko Kudo, Hirokazu Arakawa, Etsuro Ito, Masashi Sanada, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi

BLOOD 120 ( 21 ) 2012年11月

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Comprehensive Profiling of Somatic Mutations Which Define Primary Disease and Relapse in Various Acute Leukemia Subtypes

Vikas Madan, Wen-Wen Chien, Ding Ling Wen, Manoj Garg, Norimichi Hattori, Sun Qiaoyang, Henry Yang, Yasunobu Nagata, Kenichi Yoshida, Masashi Sanada, Yusuke Okuno, Tamara Alpermann, Ezhilarasi Chendamarai, Saravanan Ganesan, Daniel Nowak, Tsuyoshi Nakamaki, Norihiko Kawamata, Takayuki Ikezoe, Kow Yin Kham Shirley, Jairo Matthews, Liu Lizhen, Meng Xuan, Lim Su Lin, Olga Blau, Steven M. Kornblau, Michael Andreeff, Shigeru Tomoyasu, Wolf-Karsten Hofmann, Allen Yeoh, Seishi Ogawa, Vikram Mathews, Torsten Haferlach, Lee-Yung Shih, Phillip Koeffler

BLOOD 120 ( 21 ) 2012年11月

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Molecular Diversity Detected by Whole Exome Sequencing in Chronic Myelomonocytic Leukemia

Edward P. Evans, Satoru Miyano, Yasunobu Nagata, Yuichi Shiraishi, Kenichi Chiba, Masashi Sanada, Bartlomiej P. Przychodzen, Ines Gomez-Segui, Kathryn M. Guinta, Manuel G. Afable, Yogen Saunthararajah, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Seishi Ogawa, Hideki Makishima

BLOOD 120 ( 21 ) 2012年11月

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Molecular Diversity Detected by Whole Exome Sequencing in Chronic Myelomonocytic Leukemia

Basel Rouphail, Kenichi Yoshida, Holleh D. Husseinzadeh, Edward P. Evans, Satoru Miyano, Yasunobu Nagata, Yuichi Shiraishi, Kenichi Chiba, Masashi Sanada, Bartlomiej P. Przychodzen, Ines Gomez-Segui, Kathryn M. Guinta, Manuel G. Afable, Yogen Saunthararajah, Mikkael A. Sekeres, Jaroslaw P. Maciejewski, Seishi Ogawa, Hideki Makishima

BLOOD 120 ( 21 ) 2012年11月

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Karyotypic and Genetic Abnormalities Associated with Clonal Evolution in Paroxysmal Nocturnal Hemoglobinuria

Hideki Makishima, Kenichi Yoshida, Michael J. Clemente, Masashi Sanada, Yasunobu Nagata, Manuel G. Afable, Andres Jerez, Kenichi Chiba, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 120 ( 21 ) 2012年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

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Recurrent Mutations of Multiple Components of Cohesin Complex in Myeloid Neoplasms

Ayana Kon, Lee-Yung Shih, Masashi Minamino, Masashi Sanada, Yuichi Shiraishi, Yasunobu Nagata, Kenichi Yoshida, Yusuke Okuno, Masashige Bando, Shumpei Ishikawa, Aiko Sato-Otsubo, Genta Nagae, Claudia Haferlach, Daniel Nowak, Yusuke Sato, Tamara Alpermann, Masao Nagasaki, Teppei Shimamura, Hiroko Tanaka, Kenichi Chiba, Ryo Yamamoto, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Tsuyoshi Nakamaki, Ken Ishiyama, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Shigeru Chiba, Hiraku Mori, Hiromitsu Nakauchi, H. Phillip Koeffler, Hiroyuki Aburatani, Torsten Haferlach, Katsuhiko Shirahige, Satoru Miyano, Seishi Ogawa

BLOOD 120 ( 21 ) 2012年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

DOI： 10.1182/blood.V120.21.782.782

Web of Science

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Biological Analysis of SRSF2 Mutations in Leukemogenesis

Manabu Matsunawa, Masashi Sanada, Ryo Yamamoto, Kenichi Yoshida, Yasunobu Nagata, Ayana Kon, Tetsuichi Yoshizato, Makoto Otsu, Hiromitsu Nakauchi, Seishi Ogawa

BLOOD 120 ( 21 ) 2012年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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TET2 Mutations Revealed by Whole Genome Sequencing in Adult T-Cell Leukemia.

Yasunobu Nagata, Aiko Sato, Ayana Kon, Yusuke Okuno, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Kenichi Yoshida, Masashi Sanada, Atae Utsunomiya, Kazunari Yamaguchi, Kouichi Oshima, Shuichi Miyawaki, Akira Kitanaka, Satoru Miyano, Toshiki Watanabe, Seishi Ogawa

BLOOD 120 ( 21 ) 2012年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Whole Exome Sequencing to Predict Response to Hypomethylating Agents in MDS

Holleh D. Husseinzadeh, Edward P. Evans, Kenichi Yoshida, Hideki Makishima, Andres Jerez, Matthew Ruffalo, Yuichi Shiraishi, Satoru Miyano, Masashi Sanada, Kenichi Chiba, Yasunobu Nagata, Ines Gomez-Segui, Bartlomiej P. Przychodzen, Candice Wenzell, Manuel G. Afable, Yogen Saunthararajah, Anjali Advani, Mikkael A. Sekeres, Seishi Ogawa, Jaroslaw P. Maciejewski

BLOOD 120 ( 21 ) 2012年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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神経芽腫におけるエピジェネティック関連遺伝子の網羅的ゲノム解析(Genome-wide analysis of epigenetic regulation genes in neuroblastoma)

星野論子, 西村力, 奥野友介, 樋渡光輝, 永田安伸, 吉田健一, 真田昌, 白石友一, 宮野悟, 林泰秀, 小川誠司, 滝田順子

日本癌学会総会記事 71回 384 - 384 2012年8月

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記述言語：英語出版者・発行元：日本癌学会

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次世代シークエンサーを用いたユーイング肉腫発生の分子生物学的検討(Exome Sequencing of the Ewing's sarcoma family of tumors)

樋渡光輝, 西村力, 吉田健一, 白石友一, 奥野友介, 大久保淳, 永田安伸, 五十嵐隆, 宮野悟, 林泰秀, 小川誠司, 滝田順子

日本癌学会総会記事 71回 547 - 547 2012年8月

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記述言語：英語出版者・発行元：日本癌学会

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Frequent splicing pathway mutations and aberrant RNA splicing in myelodysplasia

Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak, Yasunobu Nagata, Ryo Yamamoto, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masao Nagasaki, George Chalkidis, Yutaka Suzuki, Masashi Shiosaka, Ryoichiro Kawahata, Tomoyuki Yamaguchi, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee-Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

CANCER RESEARCH 72 2012年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.AM2012-5119

Web of Science

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Mutations of cohesin genes in myeloid malignancy

Ayana Kon, Masashi Sanada, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Yusuke Sato, Aiko Sato-Otsubo, Masao Nagasaki, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Shuichi Miyawaki, H. Phillip Koeffler, Lee-Yung Shih, Shigeru Chiba, Satoru Miyano, Seishi Ogawa

CANCER RESEARCH 72 2012年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.AM2012-5117

Web of Science

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GENOME-WIDE ANALYSIS OF COPY NUMBER ALTERATIONS AND GENE MUTATIONS IN RENAL CELL CARCINOMA

Yusuke Sato, Shigektsu Maekawa, Aiko Sato, Yasunobu Nagata, Kenichi Yoshida, Yuichi Shiraishi, Tetsukazu Yoshizato, Yusuke Okuno, Hiromichi Suzuki, Masashi Sanada, Haruki Kume, Seishi Ogawa, Yukio Homma

JOURNAL OF UROLOGY 187 ( 4 ) E178 - E179 2012年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：ELSEVIER SCIENCE INC

Web of Science

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Integrated genetic analysis of clear cell renal cell carcionoma

Yusuke Sato, Shigekatsu Mekawa, Yasunobu Nagata, Kenichi Yoshida, Aiko Sato, Yusuke Okuno, Yuichi Shiraishi, Tetsuichi Yoshizato, Hiromichi Suzuki, Masashi Sanada, Haruki Kume, Yukio Homma, Seishi Ogawa

CANCER RESEARCH 72 2012年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.AM2012-2092

Web of Science

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Integral view of copy number alteration and commonly targeted genes in MDS found a new aspect of correlation and interrelationship with mutated components of the RNA splicing machinery

Yasunobu Nagata, Masashi Sanada, Kenichi Yoshida, Ayana Kon, Yusuke Sato, Aiko Sato, Yuichi Shiraishi, Hiraku Mori, Satoru Miyano, Lee -Yung Shih, Syuichi Miyawaki, Shigeru Chiba, H. Phillip Koeffler, Seishi Ogawa

CANCER RESEARCH 72 2012年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.AM2012-5122

Web of Science

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Mutational Spectrum Analysis of Interesting Correlation and Interrelationship Between RNA Splicing Pathway and Commonly Targeted Genes in Myelodysplastic Syndrome

Yasunobu Nagata, Masashi Sanada, Ayana Kon, Kenichi Yoshida, Yuichi Shiraishi, Aiko Sato-Otsubo, Hiraku Mori, Ken Ishiyama, Mamiko Sakata-Yanagimoto, Naoshi Obara, Masao Nagasaki, Shuichi Miyawaki, Shigeru Chiba, Satoru Miyano, Shih Lee Yung, H. Phillip Koeffler, Seishi Ogawa

BLOOD 118 ( 21 ) 126 - 126 2011年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

DOI： 10.1182/blood.V118.21.273.273

Web of Science

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Functional Analysis of SRSF2 Mutations in Myelodysplastic Syndromes and Related Disorders

Ayana Kon, Masashi Sanada, Kenichi Yoshida, Yasunobu Nagata, Yuichi Shiraishi, Yusuke Sato, Aiko Sato-Otsubo, Ryo Yamamoto, Masao Nagasaki, Yutaka Suzuki, Tomoyuki Yamaguchi, Makoto Otsu, Sumio Sugano, Shigeru Chiba, H. Phillip Koeffler, Lee-Yung Shih, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

BLOOD 118 ( 21 ) 743 - 743 2011年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Frequent Pathway Mutations of Splicing Machinery in Myelodysplasia

Kenichi Yoshida, Masashi Sanada, Yuichi Shiraishi, Daniel Nowak, Yasunobu Nagata, Ryo Yamamoto, Yusuke Sato, Aiko Sato-Otsubo, Ayana Kon, Masao Nagasaki, George Chalkidis, Yutaka Suzuki, Makoto Otsu, Naoshi Obara, Mamiko Sakata-Yanagimoto, Ken Ishiyama, Hiraku Mori, Florian Nolte, Wolf-Karsten Hofmann, Shuichi Miyawaki, Sumio Sugano, Claudia Haferlach, H. Phillip Koeffler, Lee-Yung Shih, Torsten Haferlach, Shigeru Chiba, Hiromitsu Nakauchi, Satoru Miyano, Seishi Ogawa

BLOOD 118 ( 21 ) 212 - 212 2011年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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ダウン症候群に合併した一過性骨髄増殖症(TAM)および急性巨核芽球性白血病(AMKL)の全エクソンシーケンス

吉田健一, 土岐力, 朴明子, 永田安伸, 王汝南, 白石友一, 真田昌, 昆彩菜, 佐藤亜衣子, 長崎正朗, 宮野悟, 金兼弘和, 川上清, 加藤剛二, 小島勢二, 林泰秀, 伊藤悦朗, 小川誠司

小児がん 48 ( プログラム・総会号 ) 217 - 217 2011年11月

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記述言語：日本語出版者・発行元：(NPO)日本小児がん学会

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Genome-wide analysis of copy number alternations and gene mutations in renal cell carcinoma

Yusuke Sato, Aiko Matsubara, Yasunobu Nagata, Kenichi Yoshida, Masashi Sanada, Haruki Kume, Yukio Homma, Seishi Ogawa

CANCER RESEARCH 71 2011年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.AM2011-4702

Web of Science

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Whole exome analysis of myelodysplastic syndromes

Kenichi Yoshida, Masashi Sanada, Yasunobu Nagata, Ryoichiro Kawahata, Motohiro Kato, Aiko Matsubara, Jyunko Takita, Hiraku Mori, Daniel Nowak, Wolf-Karsten Hofmann, Takayuki Ishikawa, Ken Ishiyama, Shuichi Miyawaki, Naoshi Obara, Shigeru Chiba, Seishi Ogawa

CANCER RESEARCH 71 2011年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.AM2011-925

Web of Science

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Profiling of multiple gene mutations in myelodysplastic syndromes using high-throughput resequenceing combined with barcode labeling

Yasunobu Nagata, Masashi Sanada, Kenichi Yoshida, Yusuke Sato, Takeo Nakaya, Aiko Matsubara, Ken Ishiyama, Syuichi Miyawaki, Naoshi Obara, Shigeru Chiba, Lee-Yung Shih, H. Phillip Koeffler, Seishi Ogawa

CANCER RESEARCH 71 2011年4月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER ASSOC CANCER RESEARCH

DOI： 10.1158/1538-7445.AM2011-4849

Web of Science

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Whole Exome Analysis of Myelodysplastic Syndromes Using Next-Generation Resequencing Technology

Kenichi Yoshida, Masashi Sanada, Yasunobu Nagata, Ryoichiro Kawahata, Motohiro Kato, Aiko Matsubara, Jyunko Takita, Hiraku Mori, Ken Ishiyama, Takayuki Ishikawa, Shuichi Miyawaki, Naoshi Obara, Shigeru Chiba, Seishi Ogawa

BLOOD 116 ( 21 ) 134 - 134 2010年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Profiling of Multiple Gene Mutations In Myelodysplastic Syndromes Using High-Throughput Resequenceing Combined with Barcode Labeling

Yasunobu Nagata, Masashi Sanada, Kenichi Yoshida, Takeo Nakaya, Aiko Matsubara, Naoshi Obara, Ken Ishiyama, Shuichi Miyawaki, Jyunko Takita, Shigeru Chiba, Lee-Yung Shih, H. Phillip Koeffler, Seishi Ogawa

BLOOD 116 ( 21 ) 1635 - 1635 2010年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Molecular monitoring of ERG and BAALC as minimal residual disease markers in patients with acute leukemia

Yuho Najima, Kazuteru Ohashi, Kazuhiko Kakihana, Takut Kikuchi, Yasunobu Nagata, Chihiro Sakurai, Toshimitsu Ueki, Takeshi Kobayashi, Takuya Yamashita, Machiko Kawamura, Hideki Akiyama, Hidefumi KaKu, Hisashi Sakamaki

BLOOD 110 ( 11 ) 130B - 130B 2007年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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Quantitative monitoring of T315I BCR-ABL mutation by the invader assay

Kazuhiko Kakihana, Kazuteru Ohashi, Yuho Najima, Taku Kikuchi, Yasunobu Nagata, Toshimitsu Ueki, Takeshi Kobayashi, Takuya Yamashita, Hideki Akiyama, Toshikazu Yamaguchi, Hisashi Sakamaki

BLOOD 110 ( 11 ) 207B - 207B 2007年11月

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記述言語：英語掲載種別：研究発表ペーパー・要旨（国際会議）出版者・発行元：AMER SOC HEMATOLOGY

Web of Science

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▼全件表示

産業財産権

Ｔ細胞リンパ腫の検査方法

小川誠司, 永田安伸, 片岡圭亮, 下田和哉, 北中明

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出願番号：特願2014-191287 出願日：2014年9月

公開番号：特開2016-59348 公開日：2016年4月

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受賞

日本癌学会奨励賞

2018年10月

永田安伸

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日本血液学会奨励賞

2014年10月

永田安伸

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東京大学医師会医学賞

2013年3月

永田安伸

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共同研究・競争的資金等の研究課題

クローン構造解析による骨髄異形成症候群から白血病発症までの分子病態の解明

研究課題/領域番号：20K17412 2020年4月 - 2023年3月

日本学術振興会科学研究費助成事業若手研究

永田安伸

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配分額：4290000円（直接経費：3300000円、間接経費：990000円）

遺伝子変異を持つ実際の患者に最も有効な治療法を選択する手法は未だ定まっていないため、経時的試料を解析することで、腫瘍化を促進させ最終的に白血病に進展する腫瘍発症メカニズムを明らかにし、新たな治療戦略の構築に資することを目指している。
これまでの具体的な進捗内容は、特徴的な染色体異常を有している典型的症例の試料収集が可能であった。具体的には200症例程度のMDSから実際に急性白血病に進展している症例の蓄積が可能であり、パイロットケースとして24試料の解析を行った。次世代シークエンサーで解析し体細胞性変異を抽出、白血病発症前後でそれらを比較することで消失するクローン、拡大するクローンの同定が可能であった。
少数例ではあるものの着実に目的達成に向けて想定した手法が問題なく稼働することを確認できた点は意義があると考えられる。今後は解析症例数を増やし、さらなるクローン進化の特徴を明らかにすることでより統計学的検出力を高めていく。
遺伝子異常を特異的に阻害もしくは活性化する抗がん剤の開発が進んでおり、新たに保険適用となったFLT3阻害剤やBCL2阻害剤など保険収載され実際の臨床現
場でも使用可能になっている。これらは患者ごとのサブグループ解析において、良好群と不良群に分けられ、遺伝子異常の有無により治療反応性が異なる可能性
が示唆されている。今後、これらの治療反応を遺伝子異常を用いて予測し、個々の患者における最適な治療法選択の一助になるという点で非常に重要性が高い。

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骨髄異形成症候群における病初期クローンメカニズムの解明

研究課題/領域番号：26893127 2014年8月 - 2016年3月

日本学術振興会科学研究費助成事業研究活動スタート支援

永田安伸

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配分額：2990000円（直接経費：2300000円、間接経費：690000円）

再生不良性貧血から骨髄異形成症候群に進展した全22症例を全エクソン解析した結果、66個の遺伝子変異を認めた。これまで報告のあるPIGAに加え、BCOR,BCORL1など骨髄腫瘍で既知の遺伝子が、新たに再生不良性貧血でも変異していた。数十年にわたる時系列解析を行った結果、再生不良性貧血時には数％と微小であったクローンが、骨髄異形成症候群を発症するころには数十％まで拡大し、SETBP1遺伝子のようなら新規の遺伝子変異を獲得していることが明らかとなった。このように複雑なクローン構造の変化が病勢の進行に関与していることが示唆された。

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骨髄異形成症候群における網羅的遺伝子変異解析に関する研究

研究課題/領域番号：11J04875 2011年 - 2013年

日本学術振興会科学研究費助成事業特別研究員奨励費

永田安伸

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配分額：1900000円（直接経費：1900000円）

骨髄異形成症候群の患者29例について全エクソン解析を行い、RNAスプライシングに関わる異常を含む様々な機能的パスウェイを有する遺伝子が同定された。また本解析で発見された以外にも腫瘍化に関わる遺伝子群が報告されており、高頻度に変異し腫瘍化に直接かかわる遺伝子104個を抽出し944例という多数症例について標的シークエンス解析を行った。
遺伝子異常は99個の遺伝子、864症例(91.5%)に認められ、1症例あたり3個の変異/欠失が確認された。10%以上の頻度で変異していた遺伝子は、SF3B1, TET2, ASXL1, SRSF2, DNMT3A, RUNX1の6個であり、有意に変異が認められたのは47個の遺伝子であった。これらは様々な機能的パスウェイに分類され、最も高頻度であったのはRNAスプライシング、64%であり、続いてDNAメチル化、クロマチン修飾、転写因子、シグナル伝達の順であった。
しかし、最も重要で新たに得られた知見は100以上の複数の遺伝子異常の状況が判明し、それらがMDS患者の臨床決断を促すための予後予測モデルを改善させたことである。実際に複数の遺伝子変異/欠失と予後には相関が認められ、今までにないモデルを構築する助けとなった。COX回帰によって遺伝学的因子が評価され、LASSO法の正則化によりモデル作成に関わる因子が決定された。年齢や性別、IPSS-Rに用いられるような臨床的な指標と予後に有意な影響を及ぼす14個の遺伝学的な指標を組み合わせることで新たに4つのリスクグループを区別し、有意に生存率を分類することが可能であった。赤池情報量規準などを用いて、臨床指標(IPSS-R)や遺伝学的指標をそれぞれ単独で用いた場合と比較した場合、このモデルは最も鋭敏に予後を分類することが判明した。

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