RUNX1とエピジェネティック制御機構破綻の協調作用によるMDS発症機構の解明

• Project Area: Molecular mechanisms of cell fate determination in the cells that undergo stepwise differentiation to multiple pathways
• Project/Area Number: 25118716
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo University
• Principal Investigator: 原田 浩徳 順天堂大学, 医学部, 准教授 (10314775)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: RUNX1 / EZH2 / 骨髄異形成症候群 / RUNX3 / ASXL1

Outline of Annual Research Achievements

本研究は，RUNX1とエピジェネティック制御機構破綻の協調作用によって発症する造血器腫瘍，特に骨髄異形成症候群（MDS）の分子発症機構の解明を目指すものである。
研究代表者はこれまでに，RUNX1遺伝子のゲノム異常が幹細胞分化障害・腫瘍原性を有し，造血器腫瘍発症の中心的役割を担っていることを解析・報告してきた。しかしRUNX1遺伝子異常単独ではvivoでの造血器腫瘍発症には至らない。したがって，さらなる遺伝子の異常が関わっていると考えられ，MDS発症への関与が強く示唆されるエピジェネティック制御因子に着目した。自験症例では，RUNX1変異，RUNX3高発現，BMI1高発現，EZH2低発現・高発現などが様々な組み合わせで認められ，またHBO1異常が関与する白血病症例を同定したことから，エピジェネティック制御因子異常がRUNX1と協調してMDS発症に関わっていることが強く示唆された。そこで本研究では，患者におけるRUNX1とエピジェネティック制御因子の変異・発現異常を検索し，これらのin vitroおよびin vivoでの機能を解析することにより，正常・異常RUNX1とエピジェネティック制御因子の相互作用によるMDSの分子発症機序解明を目指している。
昨年度の準備に引き続き、目的遺伝子をレトロウイルスにより臍帯血由来CD34陽性細胞に導入し，各種サイトカイン存在下培養して分化･増殖能、生存率，自己複製能について検討を行った。また同定した遺伝子異常を共同研究によりマウスへ導入し，in vivo生物学的機能を解析した。その結果，RUNX1変異を中心としたMDS/AMLの分子発症機序に関して，RUNX1変異とBMI1，EZH2，ASXL1，DNA修復，CDC25C，HMGA2等との協調作用により発症に到ることをヒトCD34陽性細胞およびマウスモデルを用いて検証した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A C-terminal mutant of CCAAT-enhancer-binding protein α (C/EBPα-C(m)) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-C(m). (2015)
  • Author(s): Togami K, Kitaura J, Uchida T, Inoue D, Nishimura K, Kawabata KC, Nagase R, Horikawa S, Izawa K, Fukuyama T, Nakahara F, Oki T, Harada Y, Harada H, Aburatani H, Kitamura T.
  • Journal Title: Exp Hematol. Volume: 43(4) Issue: 4 Pages: 300-308
  • DOI: 10.1016/j.exphem.2014.11.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS. (2015)
  • Author(s): Inoue D, Kitaura J, Matsui H, Hou HA, Chou WC, Nagamachi A, Kawabata KC, Togami K, Nagase R, Horikawa S, Saika M, Micol JB, Hayashi Y, Harada Y, Harada H, Inaba T, Tien HF, Abdel-Wahab O, Kitamura T.
  • Journal Title: Leukemia Volume: 29(4) Issue: 4 Pages: 847-57
  • DOI: 10.1038/leu.2014.301
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recent advances in myelodysplastic syndromes: molecular pathogenesis and its implications for targeted therapies (2015)
  • Author(s): Harada H, Harada Y
  • Journal Title: Cancer Sci. Volume: 106 Issue: 4 Pages: 329-336
  • DOI: 10.1111/cas.12614
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hmga2 is a direct target gene of RUNX1 and regulates expansion of myeloid progenitors in mice (2014)
  • Author(s): Lam K, Muselman A, Du R, Harada Y, Scholl AG, Yan M, Matsuura S, Weng S, Harada H, Zhang DE
  • Journal Title: Blood Volume: 124 Issue: 14 Pages: 2203-2212
  • DOI: 10.1182/blood-2014-02-554543
  • Peer Reviewed / Open Access
• [Journal Article] Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells. (2014)
  • Author(s): Nakahara F, Kitaura J, Uchida T, Nishida C, Togami K, Inoue D, Matsukawa T, Kagiyama Y, Enomoto Y, Kawabata KC, Chen-Yi L, Komeno Y, Izawa K, Oki T, Nagae G, Harada Y, Harada H, Otsu M, Aburatani H, Heissig B, Hattori K, Kitamura T.
  • Journal Title: Blood Volume: 123(25) Issue: 25 Pages: 3932-42
  • DOI: 10.1182/blood-2013-01-476747
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients (2014)
  • Author(s): Sakurai M, Kunimoto H, Watanabe N, Fukuchi Y, Yuasa S, Yamazaki S, Nishimura T, Sadahira K, Fukuda K, Okano H, Nakauchi H, Morita Y, Matsumura I, Kudo K, Ito E, Ebihara Y, Tsuji K, Harada Y, Harada H, Okamoto S, Nakajima H
  • Journal Title: Leukemia Volume: 28 Issue: 12 Pages: 2344-54
  • DOI: 10.1038/leu.2014.136
  • Peer Reviewed / Open Access
• [Journal Article] Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukemic transformation. (2014)
  • Author(s): Sashida, G., Harada, H., Matsui, H., Oshima, M., Yui, M., Harada, Y., Tanaka, S., Mochizuki-Kashio, M., Wang, C., Saraya, A., Muto, T., Hayasi, Y., Suzuki, K., Nakajima, H., Inaba, T., Koseki, H., Huang, G., Kitamura, T. and Iwama, A.
  • Journal Title: Nat. Commun. Volume: 5 Issue: 1 Pages: 5177-5177
  • DOI: 10.1038/ncomms5177
  • Peer Reviewed / Open Access
• [Journal Article] Hes1 up-regulation contributes to the development of FIP1L1-PDGFRA-positive leukemia in blast crisis. (2014)
  • Author(s): Uchida T, Kawabata KC, Kitamura T., et al.
  • Journal Title: Exp Hematol. Volume: S0301-472X(14) Issue: 5 Pages: 56-3
  • DOI: 10.1016/j.exphem.2014.01.009
  • Peer Reviewed / Open Access
• [Journal Article] Recurrent CDC25C mutations drive malignant transformation in FPD/AML (2014)
  • Author(s): Yoshimi A, Toya T, Kawazu M, Ueno T, Tsukamoto A, Iizuka H, Nakagawa M, Nannya Y, Arai S, Harada H, Usuki K, Hayashi Y, Ito E, Kirito K, Nakajima H, Ichikawa M, Mano H, Kurokawa M
  • Journal Title: Nature communications Volume: 5 Issue: 1 Pages: 4770-4770
  • DOI: 10.1038/ncomms5770
  • Peer Reviewed / Open Access
• [Journal Article] 【血液疾患とクローン性】 造血器腫瘍のクローン性進展 骨髄異形成症候群の病型悪化とクローン性進展 (2014)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液フロンティア Volume: 24(6) Pages: 895-902
• [Journal Article] 赤血球造血と疾患をめぐる最近の進歩】 MDSに対する薬物療法の進歩 (2014)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液内科 Volume: 68(5) Pages: 616-623
• [Journal Article] 骨髄異形成症候群におけるRUNX1変異とBMI1過剰発現の協調作用 (2014)
  • Author(s): 原田結花，北村俊雄，原田浩徳
  • Journal Title: 血液内科 Volume: 68(6) Pages: 805-13
  • NAID: 40020139595
• [Journal Article] 骨髄系造血器腫瘍発症の分子機構 (2014)
  • Author(s): 北村俊雄，井上大地，中原史雄，大河内直子，加藤菜穂子，戸上勝仁，内田智之，鍵山侑希，川畑公人，永瀬玲奈，堀川小百合，林 康貴，齋賀真言，伊沢久未，沖 俊彦，千葉 滋，原田結花，原田浩徳，北浦次郎
  • Journal Title: 臨床血液 Volume: 55(10) Pages: 1715-1723
  • NAID: 130004696062
  • Peer Reviewed
• [Journal Article] RUNX1/AML1 mutant collaborates with BMI1 overexpression in tnedevelopment of human and murine myelodysplastic syndromes. (2013)
  • Author(s): 原田結花、井上大地, 他
  • Journal Title: Blood Volume: 128(3) Issue: 17 Pages: 3434-3446
  • DOI: 10.1182/blood-2012-06-434423
  • Peer Reviewed
• [Journal Article] High early death rate in elderly patients with acute promyelocytic leukemia treated with all-trans retinoic acid combined chemotherapy (2013)
  • Author(s): Imagawa J, Harada Y, Shimomura T, Tanaka H, Okikawa Y, Harada H
  • Journal Title: Int J Hematol Volume: vol. 98(2) Issue: 2 Pages: 264-266
  • DOI: 10.1007/s12185-013-1390-0
  • NAID: 10031194747
  • Peer Reviewed
• [Journal Article] Myelodysplastic syndromes are induced by histone methylation-altering ASXL1 mutations. (2013)
  • Author(s): Inoue, D
  • Journal Title: J. Clin. Invest. Volume: 123 Issue: 11 Pages: 4627-4640
  • DOI: 10.1172/jci70739
  • Peer Reviewed
• [Journal Article] MDSに対するメチル化阻害剤による治療の現状と展望 (2013)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液内科 Volume: 66(3) Pages: 316-322
• [Journal Article] 低リスクMDSに対するレナリドミド (2013)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液内科 Volume: 67(3) Pages: 305-312
• [Journal Article] CMML発症のゲノム異常 (2013)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液内科 Volume: 67(5) Pages: 631-637
  • NAID: 40019901709
• [Presentation] 機能獲得型RUNX1変異による骨髄異形成症候群の発症機序 (2015)
  • Author(s): 原田浩徳
  • Organizer: 第19回造血器腫瘍研究会
  • Place of Presentation: グランテはがくれ（佐賀県佐賀市）
  • Year and Date: 2015-01-23 – 2015-01-24
• [Presentation] A randamized study to determine the opitimal dose of darbepoetin alfa in patients with low- or intermediate-1 risk myelodysplastic syndromes (2014)
  • Author(s): Harada H, Shibayama H, Jang JH, Shimazaki R, Mitani K, Sawada K, Kim H-J
  • Organizer: The 56th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS (2014)
  • Author(s): 9.Inoue D, Matsui H, How HA, Chou WC, Nagamachi A, Kitaura J, Kawabata KC, Togami K, Nagase R, Horikawa S, Saika M, Micol JB, Hayashi Y, Harada H, Tien HF, Abdel-Wahab O, Kitamura T
  • Organizer: The 56th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] C-terminal truncation type of RUNX1 mutants induce MDS/AML via gain-of-function mechanisms (2014)
  • Author(s): Harada H, Harada Y, Inoue D, Ding Y, Sashida G, Iwama A, Nakajima H, Tanaka J, KomatsuN, Kitamura T
  • Organizer: The 76th Annual Meetingof the Japanese Society of Hematology
  • Place of Presentation: 大阪国際会議場（大阪市北区）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Impaired platelet function in FPD/AML patients (2014)
  • Author(s): Sakurai M, Watanabe N, Kunimoto H, Fukuchi Y, Sadahira K, Abe D, Soma S, Ito E, Harada Y, Harada H, Okamoto S, Nakajima H
  • Organizer: The 76th Annual Meetingof the Japanese Society of Hematology
  • Place of Presentation: 大阪国際会議場（大阪市北区）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 機能獲得型RUNX1変異による骨髄異形成症候群の発症機序 (2014)
  • Author(s): 原田浩徳
  • Organizer: 2014新学術領域細胞運命制御班会議
  • Place of Presentation: 東京大学医科学研究所講堂（東京都港区）
  • Year and Date: 2014-09-02 – 2014-09-04
• [Presentation] C-terminal truncation type of RUNX1 mutants induce MDS/AML via gain-of-function mechanisms (2014)
  • Author(s): Harada H, Harada Y, Inoue D, Sashida G, Iwama A, Nakajima H, KomatsuN, Kitamura T
  • Organizer: ISEH 43rd Annual Scientific Meeting
  • Place of Presentation: Montreal (Canada)
  • Year and Date: 2014-08-21 – 2014-08-24
• [Presentation] Modeling and targeting MLL-PTD/RUNX1 related MDS/AML in mouse. (2014)
  • Author(s): Hayashi Y, Yue Z, Yan X, Sashida G, Xu Z, Harada H, Xiao Z, Huang G
  • Organizer: H 43rd Annual Scientific Meeting
  • Place of Presentation: Montreal (Canada)
  • Year and Date: 2014-08-21 – 2014-08-24
• [Presentation] 骨髄異形成症候群の分子病態と治療 (2014)
  • Author(s): 原田浩徳
  • Organizer: 第12回日本臨床腫瘍学会学術集会教育講演
  • Place of Presentation: 福岡国際会議場（福岡市博多区）
  • Year and Date: 2014-07-17 – 2014-07-19
  • Invited
• [Presentation] Recurrent CDC25C mutations drive malignant transformation in FPD/AML (2014)
  • Author(s): Yoshimi A, Toya T, Kawazu M, Ueno T, Tsukamoto A, Iizuka H, Nakagawa M, Nannya Y, Arai S, Ichikawa M, Harada H, Usuki K, Hayashi Y, Ito E, Kirito K, Nakajima H, Mano H, Kurokawa M
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: SanDiego (USA)
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] RUNX1/AML1 mutants collaborate with BMI1 in the development of myelodysplastic syndromes (2013)
  • Author(s): Harada H, Harada Y, Inoue D, Kitamura T
  • Organizer: EMBO Workshop RUNX transcription factors in development & disease (19th International RUNX Workshop)
  • Place of Presentation: Wilsede, Germany
  • Invited
• [Presentation] アザシチジンによるMDS治療．［ランチョンセミナー：骨髄異形成症候群（MDS）の分子病態、診断と治療］ (2013)
  • Author(s): 原田浩徳
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台
  • Invited
• [Presentation] A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study) (2013)
  • Author(s): Kobayashi T, Nannya Y, Ichikawa M, Kohara T, Kobune M, Harada H, Yonemura Y, Matsuda A, Kawabata H, Tohyama K, Miyazaki Y, Kurokawa M
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo, Japan
• [Presentation] Preliminary results of a randamized dose-finding study of darbepoetin alfa in MDS in Japan and Korea (2013)
  • Author(s): Shibayama H, Harada H, Jun Ho Jang, Suzuki K, Tsudo M, Ishikawa T, Uike N, Hidaka M, Usuki K, Shimizu S, Kim Y-J, Kim H, Kizaki M, Chiba S, Nannya Y, Yonemura Y, Sawa M, Ogura H, Nakazato T, Kumagai T, Kiguchi T, Takahashi T, Irie S, Mitani K, Sawada K, et al.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo, Japan
• [Presentation] RUNX1 mutant collaborates with BMI1 overexpression in the development of human and murine MDS/AML (2013)
  • Author(s): Harada H, Harada Y, Inoue D, Ding Y, Matsui H, Sashida G, Iwama A, Kitamura T
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo, Japan
• [Presentation] RUNX3 overexpression may participaten in the development of MDS/AML (2013)
  • Author(s): Miyama T, Harada Y, Ichinose T, Harada H
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo, Japan
• [Presentation] C-terminal-truncating ASXL1 mutations induce MDS via inhibition of PRC2 (2013)
  • Author(s): Inoue D, Kitaura J, Togami K, Nishimura K, Enomoto Y, Uchida T, Kagiyama Y, Kawabata KC, Nakahara F, Oki T, Harada H, Ochiya T, Aburatani H, Kimura H, Thol F, Heuser M, Levine RL, Abdel-Wahab O, Kitamura T
  • Organizer: The 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, USA
• [Presentation] The genetic landscape of FPD/AML revealed CDC25C mutation as a driver that promotes malignant transformation (2013)
  • Author(s): Yoshimi A, Toya T, Nakagawa M, Kawazu M, Nannya Y, Ichikawa M, Arai S, Harada H, Usuki K, Hayashi Y, Ito E, Kirito K, Nakajima H, Mano H, Kurokawa M
  • Organizer: The 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, USA
• [Book] 骨髄異形成症候群．ガイドライン外来診療2015 (2015)
  • Author(s): 原田浩徳
  • Total Pages: 694
  • Publisher: 日経メディカル開発
• [Book] エピゲノム異常と発がん 新・カラーテキスト血液病学（木崎昌弘編） (2013)
  • Author(s): 原田結花，原田浩徳
  • Total Pages: 687
  • Publisher: 中外医学社
• [Remarks] 細胞運命制御
  • URL: http://www.riken.jp/cell-fate/