骨髄異形成症候群(MDS)の分子基盤の解明

2017 Fiscal Year Annual Research Report

• Project/Area Number: 26221308
• Research Institution: Kyoto University
• Principal Investigator: 小川 誠司 京都大学, 医学研究科, 教授 (60292900)
• Co-Investigator(Kenkyū-buntansha): 古関 明彦 国立研究開発法人理化学研究所, その他, 研究員 (40225446)
• Project Period (FY): 2014-05-30 – 2019-03-31
• Keywords: 血液内科学 / 血液腫瘍学 / 骨髄異形成症候群 / 二次性白血病

Outline of Annual Research Achievements

骨髄異形成症候群(MDS)およびその関連疾患は、骨髄不全と急性骨髄性白血病への進展を特徴とする、高齢者に好発する慢性骨髄性腫瘍である。MDSの主な死因である骨髄不全および急性白血病に関して、本研究課題において昨年度までにRNAスプライシング因子、コヘシン関連分子を始めとするMDSの病態に関わる遺伝子変異に関して遺伝学的解析および機能的解析が行われ、大きな成果が得られた。本年度は、これらの研究成果を踏まえ、全ゲノムおよびRNAシーケンスを含む世界トップレベルの遺伝子解析技術とマウスモデルを駆使した手法を用いて、多様な遺伝子変異がMDSを発症させ、MDSを白血病へ進展させるメカニズムについて明らかにした。さらに治療抵抗性や予後予測に関する検討をも行った。具体的には、MDSにおける腫瘍内多様性とクローン進化を解明するために、MDSから二次性白血病にいたる過程において複数回採取された検体をゲノム解析した。その結果クローン進化の際に、2個以上の変異が蓄積することが悪性腫瘍の発症に必要であることが明らかとなった。また、MDSにおいて最も高頻度に変異が認められるRNAスプライス因子およびコヘシン遺伝子の変異については、合併する変異の解析が行われ、SF3B1変異例にはDNMT3AとJAK2変異が、SRSF2変異例にはRUNX1やTET2の変異が認められることが明らかとなった。以上の解析結果を臨床情報と併せて解析することにより、予後を規定する遺伝子変異および発現異常の臨床的なインパクトを確認した。スプライス因子の変異に関しては、マウスモデルによる基礎的な機能解析を行い、変異マウスに特徴的なスプライス異常と、造血障害が確認された。コヘシン変異のマウスモデルは、合併する変異とのマウスの交配を行い、詳細な機能解析を行っている。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

MDSにおける集団内多様性とクローン進化の解析に関しては、MDSから二次性白血病にいたる全経過において、経時的にゲノム解析を行った。その際、体細胞変異とそのアレル頻度を決定することにより、腫瘍内の亜集団の構造を詳細に推定し、予後との関連を明らかにした。これらの解析を関連の骨髄系腫瘍(MDS/MPN)についても行い、MDSにおける解析と比較検討することにより、クローン進化、およびドライバー変異の役割について、MDSと異なる遺伝子の関与を確認し、予想通りの進捗が認められた（Patel et al. Leukemia 2017）。さらには、公開データベースから同定された主要なドライバー遺伝子の変異情報を用いて、標的シーケンスを行うことにより、治療抵抗性や予後予測の解析をも行い、予想以上の成果が得られた（Yoshizato et al. BLOOD 2017, Shiozawa et al. BLOOD 2017）。変異RNAスプライシング因子およびコヘシン遺伝子の遺伝子標的の同定に関しては、当初計画された通り、変異スプライシング因子の分子メカニズムを解析するために、主要な変異の標的となっているRNAスプライシング因子について、相互作用する分子の同定を行った。コヘンシン遺伝子についても、頻度の高い病型の確認と特定の病型を呈する変異の機能的効果を検討し、高頻度に合併しうる遺伝子変異を複数明らかにし、おおむね順調に進捗している。マウスモデルの解析は、RNAスプライシング変異に関する解析はほぼ終了し、論文として発表した（Kon et al. BLOOD 2018）。コヘシン変異に関してもマウスモデルの機能解析を進め、下流のターゲット遺伝子の発見と造血細胞に及ぼす効果を確認している。

Strategy for Future Research Activity

平成29年度の成果を踏まえ、MDSにおける集団内多様性とクローン進化に関する解析は、予定通りMDSから二次性白血病にいたる全経過で、詳細に分画されたMDS試料について、引き続き全ゲノム解析を行う。特に、低リスクのMDS から高リスクのMDSへの進行および、二次性AMLにいたるクローン進化の解析を行う。これまでに、二次性AMLの症例に濃縮される遺伝子変異や高リスクMDSに濃縮される遺伝子異常を同定し論文として誌へ発表した（Makishima et al. Nature Genetics 2017）。この大きな成果に基づいて、MDS検体（200症例）を中心に追加のコホートを用いて、検証のためのドライバー遺伝子の標的遺伝子シーケンスを合計で500例以上において行う。この検証により、本邦のMDSにおける遺伝子変異の臨床的な有用性を明らかにする。次に、変異RNAスプライシング因子およびコヘシン遺伝子の遺伝子標的の同定に関しても、計画した通り主要な変異の標的となっているRNAスプライシング因子について、相互作用する分子の同定を行う（論文作成中）。またそれらのRNAスプライシングに対する機能的役割を検討する。コヘシン遺伝子についても、頻度の高い病型の確認と特定の病型を呈する変異の機能的効果を検討する。マウスモデルの解析については、RNAスプライシング変異とコヘシン変異について、高頻度に合併する遺伝子異常を有するマウスモデルと交配することにより、さらに詳細な解析を進め、下流のターゲット遺伝子の発見と造血細胞に及ぼす効果を確認する。

Research Products

• [Journal Article] Diagnosis and relapse: cytogenetically normal acute myelogenous leukemia without FLT3-ITD or MLL-PTD (2017)
  • Author(s): Chien W., Sun Q. Y., Ding L. W., Mayakonda A., Takao S., Liu L., Lim S. L., Tan K. T., Garg M., De Sousa Maria Varela A., Xiao J., Jacob N., Behrens K., Stocking C., Lill M., Madan V., Hattori N., Gery S., Ogawa S., Wakita S., Ikezoe T., Shih L. Y., Alpermann T., Haferlach T., Yang H., Koeffler H. P.
  • Journal Title: Leukemia Volume: 31 Pages: 762-766
  • DOI: 10.1038/leu.2016.343
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clonal evolution in myelodysplastic syndromes (2017)
  • Author(s): da Silva-Coelho P.,et al.
  • Journal Title: Nature communications Volume: 8 Pages: 15099
  • DOI: 10.1038/ncomms15099
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations (2017)
  • Author(s): Hoshino A., et al.
  • Journal Title: J Allergy Clin Immunol Volume: 140 Pages: 223-231
  • DOI: 10.1016/j.jaci.2016.09.029
  • Peer Reviewed
• [Journal Article] Recurrent genetic defects on chromosome 5q in myeloid neoplasms (2017)
  • Author(s): Hosono N., Makishima H., Mahfouz R., Przychodzen B., Yoshida K., Jerez A., LaFramboise T., Polprasert C., Clemente M. J., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Sanada M., Cui E., Verma A. K., McDevitt M. A., List A. F., Saunthararajah Y., Sekeres M. A., Boultwood J., Ogawa S., Maciejewski J. P.
  • Journal Title: Oncotarget Volume: 8 Pages: 6483-6495
  • DOI: 10.18632/oncotarget.14130
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diagnostic challenge of Diamond-Blackfan anemia in mothers and children by whole-exome sequencing (2017)
  • Author(s): Ichimura T., Yoshida K., Okuno Y., Yujiri T., Nagai K., Nishi M., Shiraishi Y., Ueno H., Toki T., Chiba K., Tanaka H., Muramatsu H., Hara T., Kanno H., Kojima S., Miyano S., Ito E., Ogawa S., Ohga S.
  • Journal Title: International journal of hematology Volume: 105 Pages: 515-520
  • DOI: 10.1007/s12185-016-2151-7
  • Peer Reviewed
• [Journal Article] Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia (2017)
  • Author(s): Ikeda F., Yoshida K., Toki T., Uechi T., Ishida S., Nakajima Y., Sasahara Y., Okuno Y., Kanezaki R., Terui K., Kamio T., Kobayashi A., Fujita T., Sato-Otsubo A., Shiraishi Y., Tanaka H., Chiba K., Muramatsu H., Kanno H., Ohga S., Ohara A., Kojima S., Kenmochi N., Miyano S., Ogawa S., Ito E.
  • Journal Title: Haematologica Volume: 102 Pages: e93-e96
  • DOI: 10.3324/haematol.2016.153932
  • Peer Reviewed
• [Journal Article] Dynamics of clonal evolution in myelodysplastic syndromes (2017)
  • Author(s): Makishima H., et al.
  • Journal Title: Nature genetics Volume: 49 Pages: 204-212
  • DOI: 10.1038/ng.3742
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of somatic mutation in unexplained blood cytopenia (2017)
  • Author(s): Malcovati L., Galli A., Travaglino E., Ambaglio I., Rizzo E., Molteni E., Elena C., Ferretti V. V., Catricala S., Bono E., Todisco G., Bianchessi A., Rumi E., Zibellini S., Pietra D., Boveri E., Camaschella C., Toniolo D., Papaemmanuil E., Ogawa S., Cazzola M.
  • Journal Title: Blood Volume: 129 Pages: 3371-3378
  • DOI: 10.1182/blood-2017-01-763425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immune-Mediated Hematopoietic Failure after Allogeneic Hematopoietic Stem Cell Transplantation: a Common Cause of Late Graft Failure in Patients with Complete Donor Chimerism (2017)
  • Author(s): Maruyama K., Aotsuka N., Kumano Y., Sato N., Kawashima N., Onda Y., Maruyama H., Katagiri T., Zaimoku Y., Nakagawa N., Hosomichi K., Ogawa S., Nakao S.
  • Journal Title: Biol Blood Marrow Transplant Volume: 24 Pages: 43-49
  • DOI: 10.1016/j.bbmt.2017.08.018
  • Peer Reviewed
• [Journal Article] Atypical dyskeratosis congenita diagnosed using whole-exome sequencing (2017)
  • Author(s): Monoi A., Sugawa M., Kato M., Seki M., Yoshida K., Shiraishi Y., Sakaguchi H., Ogawa S., Takita J.
  • Journal Title: Pediatr Int Volume: 59 Pages: 933-935
  • DOI: 10.1111/ped.13314
  • Peer Reviewed
• [Journal Article] Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes (2017)
  • Author(s): Muramatsu H., et al.
  • Journal Title: Genet Med Volume: 19 Pages: 8211-802
  • DOI: 10.1038/gim.2016.197.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural Determinants of the Gain-of-Function Phenotype of Human Leukemia-associated Mutant CBL Oncogene (2017)
  • Author(s): Nadeau S. A., An W., Mohapatra B. C., Mushtaq I., Bielecki T. A., Luan H., Zutshi N., Ahmad G., Storck M. D., Sanada M., Ogawa S., Band V., Band H.
  • Journal Title: J Biol Chem Volume: 292 Pages: 3666-3682
  • DOI: 10.1074/jbc.M116.772723
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia (2017)
  • Author(s): Nakata Y., Ueda T., Nagamachi A., Yamasaki N., Ikeda K. I., Sera Y., Takubo K., Kanai A., Oda H., Sanada M., Ogawa S., Tsuji K., Ebihara Y., Wolff L., Honda Z. I., Suda T., Inaba T., Honda H.
  • Journal Title: Blood Volume: 129 Pages: 2148-2160
  • Peer Reviewed
• [Journal Article] Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic KRAS (2017)
  • Author(s): Osumi T., Kato M., Ouchi-Uchiyama M., Tomizawa D., Kataoka K., Fujii Y., Seki M., Takita J., Ogawa S., Uchiyama T., Ohki K., Kiyokawa N.
  • Journal Title: Pediatr Blood Cancer Volume: 64 Pages: e26496
  • DOI: 10.1002/pbc.26469
  • Peer Reviewed / Open Access
• [Journal Article] Genomic determinants of chronic myelomonocytic leukemia (2017)
  • Author(s): Patel B. J., Przychodzen B., Thota S., Radivoyevitch T., Visconte V., Kuzmanovic T., Clemente M., Hirsch C., Morawski A., Souaid R., Saygin C., Nazha A., Demarest B., LaFramboise T., Sakaguchi H., Kojima S., Carraway H. E., Ogawa S., Makishima H., Sekeres M. A., Maciejewski J. P.
  • Journal Title: Leukemia Volume: 31 Pages: 2815-8211;2823
  • DOI: 10.1038/leu.2017.164
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Common Variable Immunodeficiency Caused by FANC Mutations (2017)
  • Author(s): Sekinaka Y., Mitsuiki N., Imai K., Yabe M., Yabe H., Mitsui-Sekinaka K., Honma K., Takagi M., Arai A., Yoshida K., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Muramatsu H., Kojima S., Hira A., Takata M., Ohara O., Ogawa S., Morio T., Nonoyama S.
  • Journal Title: Journal of clinical immunology Volume: 37 Pages: 434-8211;444
  • DOI: 10.1007/s10875-017-0396-4
  • Peer Reviewed
• [Journal Article] Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD) (2017)
  • Author(s): Sun Q. Y., et al.
  • Journal Title: Leukemia Volume: 31 Pages: 8211-10
  • DOI: 10.1038/leu.2016.160
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia (2017)
  • Author(s): Togasaki E., et al.
  • Journal Title: Blood cancer journal Volume: 7 Pages: 2017
  • DOI: 10.1038/bcj.2017.36
  • Peer Reviewed
• [Journal Article] Toll-like receptor genetic variations in bone marrow transplantation (2017)
  • Author(s): Uchino K., Mizuno S., Sato-Otsubo A., Nannya Y., Mizutani M., Horio T., Hanamura I., Espinoza J. L., Onizuka M., Kashiwase K., Morishima Y., Fukuda T., Kodera Y., Doki N., Miyamura K., Mori T., Ogawa S., Takami A.
  • Journal Title: Oncotarget Volume: 8 Pages: 45670-45686
  • DOI: 10.18632/oncotarget.17315
  • Peer Reviewed
• [Journal Article] ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a better prognosis (2017)
  • Author(s): Yamato G., Shiba N., Yoshida K., Shiraishi Y., Hara Y., Ohki K., Okubo J., Okuno H., Chiba K., Tanaka H., Kinoshita A., Moritake H., Kiyokawa N., Tomizawa D., Park M. J., Sotomatsu M., Taga T., Adachi S., Tawa A., Horibe K., Arakawa H., Miyano S., Ogawa S., Hayashi Y.
  • Journal Title: Genes Chromosomes Cancer Volume: 56 Pages: 382-393
  • DOI: 10.1002/gcc.22443
  • Peer Reviewed
• [Journal Article] The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes (2017)
  • Author(s): Yip B. H., Steeples V., Repapi E., Armstrong R. N., Llorian M., Roy S., Shaw J., Dolatshad H., Taylor S., Verma A., Bartenstein M., Vyas P., Cross N. C., Malcovati L., Cazzola M., Hellstrom-Lindberg E., Ogawa S., Smith C. W., Pellagatti A., Boultwood J.
  • Journal Title: The Journal of clinical investigation Volume: 127 Pages: 2206-2221
  • DOI: 10.1172/JCI91363
  • Peer Reviewed
• [Journal Article] Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation (2017)
  • Author(s): Yoshizato T., et al.
  • Journal Title: Blood Volume: 129 Pages: 2347-2358
  • DOI: 10.1182/blood-2016-12-754796
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Origins of myelodysplastic syndromes after aplastic anemia. (2017)
  • Author(s): Negoro E., Nagata Y., Clemente MJ., Hosono N., Shen W., Nazha A., Yoshizato T., Hirsch C., Przychodzen B., Mahfouz RZ., Kuzmanovic T., Sekeres MA., Makishima H., Ogawa S., Maciejewski JP.
  • Journal Title: Blood Volume: 130 Pages: 1953-1957
  • DOI: 10.1182/blood-2017-02-767731
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel genetic and morphologic phenotype of ARID2-mediated myelodysplasia. (2017)
  • Author(s): Sakai H, Hosono N, Nakazawa H, Przychodzen B, Polprasert C, Carraway HE, Sekeres MA, Radivoyevitch T, Yoshida K, Sanada M, Yoshizato T, Kataoka K, Nakagawa MM, Ueno H, Nannya Y, Kon A, Shiozawa Y, Takeda J, Shiraishi Y, Chiba K, Miyano S, Singh J, Padgett RA, Ogawa S, Maciejewski JP, Makishima H.
  • Journal Title: Leukemia. Volume: 32 Pages: 839-843
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition. (2017)
  • Author(s): Enane FO, Shuen WH, Gu X, Quteba E, Przychodzen B, Makishima H, Bodo J, Ng J, Chee CL, Ba R, Seng Koh L, Lim J, Cheong R, Teo M, Hu Z, Ng KP, Maciejewski J, Radivoyevitch T, Chung A, Ooi LL, Tan YM, Cheow PC, Chow P, Chan CY, Lim KH, Yerian L, Hsi E, Toh HC, Saunthararajah Y.
  • Journal Title: J Clin Invest. Volume: 127 Pages: 3527-3542
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells. (2017)
  • Author(s): Pan F, Wingo TS, Zhao Z, Gao R, Makishima H, Qu G, Lin L, Yu M, Ortega JR, Wang J, Nazha A, Chen L, Yao B, Liu C, Chen S, Weeks O, Ni H, Phillips BL, Huang S, Wang J, He C, Li GM, Radivoyevitch T, Aifantis I, Maciejewski JP, Yang FC, Jin P, Xu M.
  • Journal Title: Nat Commun. Volume: 8 Pages: 15102
  • DOI: doi: 10.1038/ncomms15102
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A Novel Genetic Mechanism of Evading Anti-tumor Immunity In Multiple Human Cancers (2017)
  • Author(s): Seishi Ogawa
  • Organizer: 2017 AACR Annual Meeting
  • Int'l Joint Research / Invited
• [Presentation] がんの免疫回避に関わる新たなメカニズムについて (2017)
  • Author(s): 小川 誠司
  • Organizer: 第54回日本臨床分子医学会学術集会
  • Invited
• [Presentation] Experimental pathology: Gene expression and gene mutation 3 (2017)
  • Author(s): Hideki Makishima
  • Organizer: The 106th Annual Meeting of the Japanese Society of Pathology
• [Presentation] The Aberrant Spliceosome Machinery (2017)
  • Author(s): Seishi Ogawa
  • Organizer: THE 14 th International SYMPOSIUM on MYELODYSPLASTIC SINDROMES
  • Int'l Joint Research / Invited
• [Presentation] Clonal hematopoiesis in aplastic anemia.-CLONAL DYNAMICS ESCAPING FROM AUTOIMMUNITY- (2017)
  • Author(s): Hideki Makishima
  • Organizer: Korean Society of Hematology
  • Int'l Joint Research / Invited
• [Presentation] 悪性腫瘍の遺伝学 (2017)
  • Author(s): 小川 誠司
  • Organizer: 芝蘭会学術講演会
  • Invited
• [Presentation] がんとゲノムの異常について (2017)
  • Author(s): 小川 誠司
  • Organizer: 第45回神戸ラボ全体研究会議
  • Invited
• [Presentation] A novel genetic and morphologic phenotype of ARID2-mediated myelodysplastic syndromes. (2017)
  • Author(s): Hitoshi Sakai, et al.
  • Organizer: 22nd Congress of European Hematology Association
  • Int'l Joint Research
• [Presentation] Transcriptome Sequencing Reveals Distinct Subtypes of Myelodysplasia with Prognostic Significance. (2017)
  • Author(s): Yusuke Shiozawa, Luca Malcovati, Anna Galli, Andrea Pellagatti, Mohsen Karimi, Aiko Sato-Otsubo, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Yuichi Shiraishi, Kenichi Chiba, Hideki Makishima, Jacqueline Boultwood, Eva Hellström Lindberg, Satoru Miyano, Mario Cazzola, Seishi Ogawa
  • Organizer: 22nd Congress of European Hematology Association
  • Int'l Joint Research
• [Presentation] MOLECULAR MARKERS PREDICTING RESPONSE TO AZACITIDINE TREATMENT FOR MYELODYSPLASTIC SYNDROMES. (2017)
  • Author(s): Yasuhito Nannya, et al.
  • Organizer: European Hematology Association
  • Int'l Joint Research
• [Presentation] Advancement of Molecular Pathogenesis in Myelodysplastic Syndromes (2017)
  • Author(s): Hideki Makishima
  • Organizer: Hematology Meeting, University of Freiburg
  • Int'l Joint Research / Invited
• [Presentation] GENETIC LANDSCAPE OF ACUTE ERYTHROID LEUKEMIA (2017)
  • Author(s): June Takeda, et al.
  • Organizer: 22nd Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] MDSにおける遺伝子変異と臨床像・予後について (2017)
  • Author(s): 小川 誠司
  • Organizer: 第7回日本骨髄不全症研究会学術集会
  • Invited
• [Presentation] 骨髄異形成症候群の分子病態 ー遺伝子変異の経時的な獲得ー (2017)
  • Author(s): 牧島秀樹
  • Organizer: 第15回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] MDSの分子プロファイリング (2017)
  • Author(s): 小川 誠司
  • Organizer: 第24回岐阜血液疾患研究会
• [Presentation] A Novel Genetic Mechanism of Evading Anti-tumor Immunity In Multiple Human Cancers (2017)
  • Author(s): Seishi Ogawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Invited
• [Presentation] A novel mechanism of antitumor immunity in multiple human cancers (2017)
  • Author(s): Seishi Ogawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Invited
• [Presentation] Integrated molecular analysis of myelodysplastic syndromes using whole genome sequencing (2017)
  • Author(s): Takashi Kanamori, Yasuhito Nannya, Kenichi Yoshida, Keisuke Kataoka, Tetsuichi Yoshizato, Hiroko Tanaka, Kenichi Chiba, Yuichi Shiraishi, Tomoki Naoe, Shigeru Chiba, Norio Aso, Yasushi Miyazaki, Satoru Miyano, and Seishi Ogawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] Efficacy of azacitidine for TP53-mutated myelodysplastic syndromes (MDS) (2017)
  • Author(s): Yasuhito Nannya, June Takeda , Shinya Sato, Yuichi Shiraishi, Kenichi Yoshida, Yusuke Shiozawa, Hideki Makishima , Shinji Nakao , Kazuma Ohyashiki , Yasushi Miyazaki , Tomoki Naoe , Satoru Miyano , Seishi Ogawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] Aplastic anemia and clonal evolution: risk factors (2017)
  • Author(s): Seishi Ogawa
  • Organizer: International Meeting on Childhood MDS and SAA
  • Int'l Joint Research / Invited
• [Presentation] U2AF2 mutations in myelodysplastic syndromes (2017)
  • Author(s): Tetsuichi Yoshizato, Yasuhito Nannya, Yoshiko Atsuta, Yusuke Shiozawa, Kenichi Yoshida, Keisuke Kataoka, Yuichi Shiraishi, Masashi Sanada, Yoshinobu Kanda, Yasushi Miyazaki, Satoru Miyano, Hideki Makishima, Seishi Ogawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] Biological characterization of DDX41 germline and somatic mutations in myeloid neoplasms. (2017)
  • Author(s): Ayana Kon, Keisuke Kataoka, June Takeda, Tetsuichi Yoshizato, Masahiro Nakagawa, Yasunori Kogure, Kenichi Yoshida, Manabu Nakayama, Haruhiko Koseki, Hideki Makishima, Seishi Ogawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] Precision medicine for early detection of clonal evolution in myelodysplastic syndromes (2017)
  • Author(s): Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, Yasuhito Nannya, Yasunobu Nagata, Yusuke Okuno, Yuichi Shiraishi, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Torsten Haferlach, Jaroslaw P. Maciejewski, Seishi Ogawa.
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
  • Invited
• [Presentation] MLL/AF9 急性骨髄性白血病における治療不応性に関わる網羅的遺 伝子解析 (2017)
  • Author(s): 小谷 槙一、片岡 圭亮、竹田 淳恵、上野 浩生、塩澤 裕介、吉里 哲一、昆 彩奈、吉田 健一、南谷 泰仁、依田 成玄、高折晃史、小川 誠司、牧島 秀樹
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] Cohesin subunit Stag2 regulates Hematopoietic Differentiation and Self-Renewal (2017)
  • Author(s): Yotaro Ochi, Ayana Kon, Kenichi Yoshida, Keisuke Kataoka, Masahiro Marshall Nakagawa, Manabu Nakayama, Haruhiko Koseki, Akifumi Takaori-Kondo, and Seishi Ogawa
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] 骨髄腫瘍におけるコヒーシン複合体変異の解析 (2017)
  • Author(s): June Takeda, et al.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Biological characterization of DDX41 germline and somatic mutations in myeloid neoplasms. (2017)
  • Author(s): Ayana Kon, Keisuke Kataoka, Hideki Makishima, June Takeda, Tetsuichi Yoshizato, Masahiro Nakagawa, Yasunori Kogure, Kenichi Yoshida, Manabu Nakayama, Haruhiko Koseki, Seishi Ogawa
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Advances in clinical and basic researches in MDS (2017)
  • Author(s): Yasuhito Nannya
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
  • Invited
• [Presentation] 骨髄異形成症候群におけるゲノム異常の段階的獲得 (2017)
  • Author(s): 牧島秀樹
  • Organizer: 第79回日本血液学会学術集会
  • Invited
• [Presentation] GENETIC LANDSCAPE OF ACUTE ERYTHROID LEUKEMIA (2017)
  • Author(s): June Takeda, et al.
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] U2AF2 mutations in myelodysplastic syndromes (2017)
  • Author(s): Tetsuichi Yoshizato, Yasuhito Nannya, Yoshiko Atsuta, Yusuke Shiozawa, Kenichi Yoshida, Makoto Onizuka, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Masashi Sanada, Hidehiro Itonaga, Yoshinobu Kanda, Yasushi Miyazaki, Satoru Miyano, Hideki Makishima, Seishi Ogawa
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Integrated molecular analysis of myelodysplastic syndromes using whole genome sequencing (2017)
  • Author(s): Yasuhito Nannya, Kenichi Yoshida, Keisuke Kataoka, Tetsuichi Yoshizato, Tomoki Naoe, Shigeru Chiba, Norio Aso, Yasushi Miyazaki, Hiroko Tanaka, Kenichi Chiba, Yuichi Shiraishi, Satoru Miyano, and Seishi Ogawa
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Specific effect of azacitidine for TP53 (+) MDS (2017)
  • Author(s): Yasuhito Nannya, June Takeda, Shinya Sato, Yusuke Shiozawa, Yuichi Shiraishi, Keisuke Kataoka, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Shigeru Chiba, Norio Asou, Hitoshi Kiyoi, Shinji Nakao, Kazuma Ohyashiki, Tomoki Naoe, Hideki Makishima, Kenichi Yoshida, Satoru Miyano, Yasushi Miyazaki, and Seishi Ogawa 
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] MLL/AF9 急性骨髄性白血病における治療不応性に関わる網羅的遺 伝子解析 (2017)
  • Author(s): 小谷 槙一、片岡 圭亮、竹田 淳恵、上野 浩生、塩澤 裕介、吉里 哲一、昆 彩奈、吉田 健一、南谷 泰仁、依田 成玄、高折晃史、小川 誠司、牧島 秀樹
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Mechanisms of the clonal evolution of MDS as revealed by single-cell sequencing. (2017)
  • Author(s): Masahiro M Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Keisuke Kataoka, Tetsuichi Yoshizato, Hideki Makishima, Kenichi Yoshida, and Seishi Ogawa
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Somatic mutation in MDS and its effect on outcome (2017)
  • Author(s): Tetsuichi Yoshizato
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
  • Int'l Joint Research / Invited
• [Presentation] Cohesin subunit Stag2 regulates Hematopoietic Differentiation and Self-Renewal (2017)
  • Author(s): Yotaro Ochi, Ayana Kon, Kenichi Yoshida, Keisuke Kataoka, Masahiro Marshall Nakagawa, Manabu Nakayama, Haruhiko Koseki, Akifumi Takaori-Kondo, and Seishi Ogawa
  • Organizer: The 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Impact of genetic abnormalities on outcome in patients with MDS after stem-cell transplantation. (2017)
  • Author(s): Tetsuichi Yoshizato
  • Organizer: The Nordic MDS Group (NMDSG) meeting 2017 autumn
  • Int'l Joint Research
• [Presentation] Mechanisms of the clonal evolution of myeloid malignancies as revealed by single-cell sequencing. (2017)
  • Author(s): Masahiro M Nakagawa, Ryosaku Inagaki, Yasuhito Nannya, Keisuke Kataoka, Tetsuichi Yoshizato, Hideki Makishima, Kenichi Yoshida, and Seishi Ogawa
  • Organizer: JCA(Japanese Cancer Association)
• [Presentation] 骨髄異形成症候群（MDS）における、胚細胞および体細胞変異 ー遺伝子変異の経時的な獲得ー (2017)
  • Author(s): 牧島秀樹
  • Organizer: 日本人類遺伝学会総会 第62回大会
  • Invited
• [Presentation] 骨髄異形成症候群（MDS）における ゲノム異常の獲得パターンとその臨床的意義 (2017)
  • Author(s): 牧島秀樹
  • Organizer: 千里ライフサイエンスセミナー L4
  • Invited
• [Presentation] Comprehensive Evaluation of DDX41 Risk Alleles in Non-Familial Cases, General Individuals, and Donor-Derived Leukemias (2017)
  • Author(s): Hideki Makishima
  • Organizer: The 59th American Society of Hematology Annual Meeting
  • Int'l Joint Research / Invited
• [Presentation] Functional and Biological Implications of CUX1 Mutations and Deletions in Myeloid Neoplasms (2017)
  • Author(s): Mai Aly, Zubaidah M Ramdzan, Yasunobu Nagata, Suresh K. Balasubramanian, Naoko Hosono, Hideki Makishima, Valeria Visconte, Bartlomiej P. Przychodzen, Cassandra M. Hirsch, Mikkael A. Sekeres, Alain Nepveu, and Jaroslaw Maciejewski
  • Organizer: The 59th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Molecular Pathogenesis of Progressive Refractoriness in MLL -Rearranged AML. (2017)
  • Author(s): Shinichi Kotani, Keisuke Kataoka, June Takeda, Hiroo Ueno, Yusuke Shiozawa, Tetsuichi Yoshizato, Ayana Kon, Kenichi Yoshida, Yasuhito Nannya, Akinori Yoda, Yuichi Shiraishi, Satoru Miyano, Akifumi Takaori-Kondo, Hideki Makishima and Seishi Ogawa.
  • Organizer: The 59th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Molecular signatures that predict response to azacitidine treatment for myelodysplastic syndromes. (2017)
  • Author(s): Yasuhito Nannya, et al.
  • Organizer: The 59th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] IDH1/2-Mutated Acute Myeloid Leukemia Has Impaired DNA Damage Response and Is Sensitive to Monotherapy with the PARP Inhibitior Olaparib. (2017)
  • Author(s): Remco J Molenaar, Tomas Radivoyevitch, Yasunobu Nagata,Bartlomiej P. Przychodzen, Hideki Makishima, Hetty E. Carraway, Sudipto Mukherjee, Mikkael A. Sekeres, Cornelis van Noorden, and Jaroslaw P. Maciejewski
  • Organizer: The 59th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Non-Random Interactions between Founder and Subclonal Mutations Shape the Clinical and Morphological Features of MDS (2017)
  • Author(s): Yasunobu Nagata, et al.
  • Organizer: The 59th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Stag2 regulates Hematopoietic Differentiation and Self-Renewal (2017)
  • Author(s): Yotaro Ochi, Ayana Kon, Kenichi Yoshida, Keisuke Kataoka, Masahiro Marshall Nakagawa, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Akifumi Takaori-Kondo, and Seishi Ogawa
  • Organizer: The 59th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] The genetic basis of del (5q) positive MDS (2017)
  • Author(s): Seishi Ogawa
  • Organizer: International Meeting “Cancer Genetics: Yesterday, Today, Tomorrow”
  • Int'l Joint Research / Invited
• [Presentation] Impact of genetic alterations on transplant outcomes for MDS (2017)
  • Author(s): Yasuhito Nannya
  • Organizer: 泌尿器分子細胞研究会
  • Invited
• [Presentation] 正常造血細胞への遺伝子異常の蓄積と急性骨髄性白血病発症機序 (2017)
  • Author(s): 牧島秀樹
  • Organizer: 第16回日本再生医療学会総会
  • Invited
• [Presentation] A novel mechanism of cancer immune evasion via the disruption of PD-L1 3’-UTR (2017)
  • Author(s): Seishi Ogawa
  • Organizer: 2018 Korean Society of Hematology International Conference & 59th Annual Meeting (ICKSH 2018)
  • Int'l Joint Research / Invited
• [Presentation] Genome-based Precision Medicine in Hematopoietic Tumors (2017)
  • Author(s): Seishi Ogawa
  • Organizer: US Japan Cancer Genomics and Personalized Medicine Symposium
  • Int'l Joint Research / Invited
• [Presentation] NGS-driven decisions in transplant for MDS (2017)
  • Author(s): Seishi Ogawa
  • Organizer: 44th Annual Meeting of the EBMT
  • Int'l Joint Research / Invited