Molecular mechanisms of myelodysplastic syndromes (MDS) using RUNX1-mutated iPS cells derived from familial MDS patients

• Project/Area Number: 24591398
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Juntendo University (2013-2014); Hiroshima University (2012)
• Principal Investigator: HARADA Hironori 順天堂大学, 医学部, 准教授 (10314775)
• Co-Investigator(Kenkyū-buntansha): HARADA Yuka 順天堂大学, 医学部, 助教 (50379848)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 家族性MDS / iPS細胞 / RUNX1変異 / 骨髄異形成症候群 / CDC25C変異

Outline of Final Research Achievements

We established RUNX1-mutated induced pluripotent stem cells (iPSs) derived from familial myelodysplastic syndromes (MDS) pedigrees. Familial MDS-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes. The familial MDS-iPSCs are thought to be a useful tool to investigate RUNX1 mutant-mediated molecular mechanisms of MDS, however, blast cells did not expand during long time culture. Therefore, additional gene abnormalities should be required to develop MDS. We investigated gene abnormalities in familial MDS patients with RUNX1-mutations using whole-exome sequencing. As a result, we identified recurrent CDC25C mutations to drive malignant transformation in familial MDS pedigrees.

Research Products

• [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] 【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: 805-813
• [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
• [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
• [Journal Article] 急性前骨髄球性白血病．特集：臨床血液学 今後の展望（2013年版）―骨髄系疾患― (2013)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 臨床血液 Volume: 54 Pages: 49-60
• [Journal Article] 治療関連白血病の病因・病態と治療 (2012)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 日本臨牀 Volume: 70 Pages: 699-703
• [Journal Article] MDSにおける遺伝子変異の臨床的意義［特集：造血不全症］ (2012)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液内科 Volume: 64 Pages: 551-556
  • NAID: 40019341774
• [Journal Article] 骨髄異形成症候群（MDS）と慢性骨髄性白血病（CML）における白血病移行の分子機構 (2012)
  • Author(s): 北村俊雄，大河内直子，井上大地，戸上勝仁，内田智之，鍵山侑希，川畑公人，千葉 滋，原田結花，原田浩徳，北浦次郎，中原史雄
  • Journal Title: 臨床血液 Volume: 53 Pages: 734-739
  • NAID: 10031073479
• [Journal Article] MDSの分子病態［特集：MDSをめぐる最近の進歩―治癒を目指して］ (2012)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液内科 Volume: 65 Pages: 300-307
  • NAID: 40019458028
• [Journal Article] RUNX1異常によるAML (2012)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 最新医学 Volume: 67 Pages: 2433-2439
• [Journal Article] Morphologic analysis in myelodysplastic syndromes with del(5q) treated with lenalidomide. A Japanese multiinstitutional study (2012)
  • Author(s): Matsuda A, Taniwaki M, Jinnai I, Harada H, Watanabe M, Suzuki K, Yanagita S, Suzuki T, Yoshida Y, Kimura A, Tsudo M, Tohyama K, Takatoku M, Ozawa K
  • Journal Title: Leuk Res Volume: (in press) Issue: 5 Pages: 575-580
  • DOI: 10.1016/j.leukres.2011.11.011
  • Peer Reviewed
• [Journal Article] Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis (2012)
  • Author(s): Oki T, Kitaura J, Watanabe-Okochi N, Nishimura K, Maehara A, Uchida T, Komeno Y, Nakahara F, Harada Y, Sonoki T, Harada H, Kitamura T
  • Journal Title: Leukemia Volume: (in press) Issue: 5 Pages: 1038-1045
  • DOI: 10.1038/leu.2011.328
  • Peer Reviewed
• [Journal Article] A sharp fluctuation in peripheral blood cells shortly after dasatinib administration (2012)
  • Author(s): Imagawa J, Tanaka H, Matsumoto K, Morita K, Harada Y, Harada H
  • Journal Title: Int J Hematol Volume: 96(2) Issue: 2 Pages: 194-199
  • DOI: 10.1007/s12185-012-1138-2
  • NAID: 10031042803
  • Peer Reviewed
• [Journal Article] 放射線発がん(骨髄異形成症候群・白血病)の分子病態,特集「放射線の人体影響～原爆・チェルノブイリの知見とフクシマ」 (2011)
  • Author(s): 原田結花, 原田浩徳
  • Journal Title: 血液フロンティア Volume: 21 Issue: 5 Pages: 1775-1781
  • DOI: 10.1111/j.1365-2141.2012.09057.x
  • Peer Reviewed
• [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): 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: ISEH 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, Suzuki K, Tsudo M, Ishikawa T, Uike N, Hidaka M, Usuki K, Shimizu S, 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
  • 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
• [Presentation] Molecular mechanisms of myelodysplastic syndromes by RUNX1/AML1 mutations (2012)
  • Author(s): Harada H, Harada Y
  • Organizer: The 3rd JSH International Symposium 2012 in Kawagoe
  • Place of Presentation: Kawagoe, Japan
  • Invited
• [Presentation] 放射線関連MDS・白血病の発症機序におけるRUNX1/AML1変異の役割「放射線障害と血液疾患」 (2012)
  • Author(s): 原田浩徳
  • Organizer: 第52回日本リンパ網内系学会総会
  • Place of Presentation: 福島
  • Invited
• [Presentation] RUNX1/AML1 mutants collaborate with BMI1 in the development of myelodysplastic syndromes (2012)
  • Author(s): Harada H, Harada Y, Inoue D, Kitamura T
  • Organizer: ISEH 41st Annual Scientific Meeting
  • Place of Presentation: Amsterdam, Netherland
• [Presentation] RUNX1/AML1 mutants collaborate with BMI1 in the development of myelodysplastic syndromes (2012)
  • Author(s): Harada H, Harada Y, Inoue D, Kitamura T
  • Organizer: The 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Sapporo, Japan
• [Presentation] RUNX1/AML1 mutants collaborate with BMI1 in the development of myelodysplastic syndromes (2012)
  • Author(s): Harada H, Inoue D, Ding Y, Imagawa J, Harada Y, Kitamura T
  • Organizer: The 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kyoto, Japan
• [Presentation] RUNX1/AML1 mutants collaborate with BMI1 in the development of myelodysplastic syndromes (MDS) / acute myeloid leukemia (AML) in a mouse BMT model (2012)
  • Author(s): Harada H, Inoue D, Doki N, Ding Y, Harada Y, Kitamura T
  • Organizer: The 54th ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta, GA, USA
• [Presentation] Impaired hematopoietic differentiation of iPSCs derived from a patient with FPD/AML (2012)
  • Author(s): Sakurai M, Kunimoto H, Watanabe N, Fukuchi Y, Sadahira K, Yuasa S, Fukuda K, Yamazaki S, Nakauchi H, Ebihara Y, Tsuji K, Ito E, Harada Y, Harada H, Okamoto S, Nakajima H
  • Organizer: The 54th ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta, GA, 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
• [Book] 造血器腫瘍とエピジェネティクス―治療への応用と新たな展開― (2012)
  • Author(s): 原田結花，原田浩徳
  • Total Pages: 251
  • Publisher: 医薬ジャーナル社
• [Book] EBM血液疾患の治療2012-2013 (2012)
  • Author(s): 原田結花，原田浩徳
  • Total Pages: 590
  • Publisher: 中外医学社