Role of epigenetic dysregulation in the pathogenesis of hematological malignancies

• Project/Area Number: 24249054
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: IWAMA Atsushi 千葉大学, 医学(系)研究科(研究院), 教授 (70244126)
• Co-Investigator(Kenkyū-buntansha): SASHIDA Goro 熊本大学, 国際先端医学研究機構, 特別招聘準教授 (70349447)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥44,980,000 (Direct Cost: ¥34,600,000、Indirect Cost: ¥10,380,000); Fiscal Year 2014: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000); Fiscal Year 2013: ¥15,470,000 (Direct Cost: ¥11,900,000、Indirect Cost: ¥3,570,000); Fiscal Year 2012: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
• Keywords: エピジェネティクス / 造血器腫瘍 / ポリコーム群遺伝子 / 骨髄異形成症候群 / 骨随異形成症候群 / ポリコーム群複合体

Outline of Final Research Achievements

We demonstrated that the polycomb gene Ezh2 is required to promote MLL-AF9-driven acute myeloid leukemia (AML) in mice (Blood 120:1107, 2012). In contrast, we also found that the hematopoietic-specific deletion of Ezh2 in mice induced heterogeneous hematopoietic malignancies, including myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasms (MDS/MPN), and T-ALL after a long latency. Furthermore, the concurrent depletion of Ezh2 and Tet2 in mice markedly accelerated the development of MDS and MDS/MPN and Ezh2 loss significantly promoted RUNX1S291fs-induced MDS (J Exp Med 210:2627, 2013; Nat Commun 5:4177, 2014). These findings support the tumor suppressor function of EZH2 in the context of myelodysplastic disorders and well correspond to the identification of recurrent inactivating mutations in EZH2 in patients with MDS, MPN, MDS/MPN, and T-ALL.

Research Products

• [Journal Article] Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development. (2014)
  • Author(s): Mishima Y, Wang C, Miyagi S, Saraya A, Hosokawa H, Mochizuki-Kashio M, Nakajima-Takagi Y, Koide S, Negishi M, Sashida G, Naito T, Ishikura T, Onodera A, Nakayama T, Tenen DG, Yamaguchi N, Koseki H, Taniuchi I, Iwama A.
  • Journal Title: Nat Commun Volume: 18 Pages: 5872-5872
  • DOI: 10.1038/ncomms6872
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Pages: 4177-4177
  • DOI: 10.1038/ncomms5177
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MDS with extramedullary erythroid hyperplasia induced by loss of Tet2 in mice. (2014)
  • Author(s): Muto T, Sashida G, Hasegawa N, Nakaseko C, Yokote K, Shimoda K and Iwama A.
  • Journal Title: Blood Volume: 17 Pages: 3336-3343
  • DOI: 10.1182/blood-2013-12-544544
  • Peer Reviewed
• [Journal Article] The TIF1β-HP1 System Maintains Transcriptional Integrity of Hematopoietic Stem Cells. (2014)
  • Author(s): Miyagi S, Koide S, Saraya A, Wendt GR, Oshima M, Konuma T, Yamazaki S, Mochizuki-Kashio M, Nakajima-Takagi Y, Wang C, Chiba T, Kitabayashi I, Nakauchi H, Iwama A.
  • Journal Title: Stem cell reports Volume: 2 Pages: 145-52
  • DOI: 10.1016/j.stemcr.2013.12.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. (2013)
  • Author(s): Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, Nagae G, Nakaseko C, Yokote K, Shimoda K, Koseki H, Suzuki Y, Sugano S, Aburatani H, Ogawa S, Iwama A.
  • Journal Title: J Exp Med. Volume: 210(12) Pages: 2627-2639
  • DOI: 10.1084/jem.20131144
  • Peer Reviewed
• [Journal Article] RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes. (2013)
  • Author(s): Harada Y
  • Journal Title: Blood Volume: in press
  • Peer Reviewed
• [Journal Article] Ezh2 augments leukemogenecity by reinforcing differentiation blockage in acute myeloid leukemia (2012)
  • Author(s): Tanaka S
  • Journal Title: Blood. Volume: 120 Pages: 1107-1117
  • DOI: 10.1182/blood-2011-11-394932
  • Peer Reviewed
• [Presentation] Epigenetic Regulation of Hematopoiesis and disease (2015)
  • Author(s): Atsushi Iwama
  • Organizer: Keystone Symposia on "Hematopoiesis"
  • Place of Presentation: Colorado, U.S.A.
  • Year and Date: 2015-02-22 – 2015-02-27
  • Invited
• [Presentation] Role of polycomb group genes in hematological malignancies (2014)
  • Author(s): Atsushi Iwama
  • Organizer: International Conference on the 19th Annual Meeting of Korean Society of Cancer Prevention
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-12-12 – 2014-12-13
  • Invited
• [Presentation] Epigenetic regulation of hematopoietic stem cells (2014)
  • Author(s): Atsushi Iwama
  • Organizer: International Forum on Stem Cells
  • Place of Presentation: Tianjin, China
  • Year and Date: 2014-11-01 – 2014-11-03
  • Invited
• [Presentation] Stem cell maintenance and amplification (2014)
  • Author(s): Atsushi Iwama
  • Organizer: The 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 大阪国際会議場、大阪府大阪市
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] Role of polycomb group genes in the pathogenesis of myeloid malignancies (2014)
  • Author(s): Atsushi Iwama
  • Organizer: EMBO Workshop "Stem Cells and Epigenetics in Cancer"
  • Place of Presentation: Hong Kong, China
  • Year and Date: 2014-10-16 – 2014-10-18
  • Invited
• [Presentation] Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders (2013)
  • Author(s): Iwama A.
  • Organizer: The 72th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
• [Presentation] Role of the polycomb group proteins in the maintenance of hematopoietic stem cells and restriction of tumor development (2012)
  • Author(s): Iwama A
  • Organizer: 41st Annual Scientific Meeting of the ISEH
  • Place of Presentation: Amsterdam
  • Invited
• [Presentation] Role of the polycomb group proteins in the maintenance of hematopoietic stem cells and restriction of tumor development. (2012)
  • Author(s): Iwama A
  • Organizer: The 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kyoto
  • Invited
• [Presentation] ヒストン修飾による造血幹細胞の機能制御
  • Author(s): 岩間厚志
  • Organizer: 第36回MCS23日本分子生物学会年会ワークショップ「細胞系譜とエピゲノムダイナミクス」
  • Place of Presentation: 神戸
• [Book] Annual Review 呼吸器 (2015)
  • Author(s): 永井厚志、巽浩一郎、桑野和善、高橋和久編
  • Publisher: 中外医学社
• [Book] Stem Cells and Cancer Stem Cells (2013)
  • Author(s): Wendt G, Nakamura S, and Iwama A.
  • Total Pages: 10
  • Publisher: Springer.