Epigenetic dysregulation in myelodysplastic syndromes in the absence of Ezh2

• Project/Area Number: 26461396
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kumamoto University
• Principal Investigator: SASHIDA GORO 熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)
• Co-Investigator(Renkei-kenkyūsha): IWAMA Atsushi 千葉大学, 大学院医学研究院, 教授 (70244126)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 骨髄異形成症候群 / 慢性骨髄増殖性腫瘍 / 骨髄線維症 / エピゲノム / ポリコーム複合体 / TET2 / RUNX1 / JAK2 / ポリコーム / がん幹細胞 / EZH2

Outline of Final Research Achievements

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by impaired hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Epigenetic regulators including TET2, DNMT3A and EZH2 are often mutated in patients with MDS. Recently, exome sequencing of blood cells from aged people without hematological malignancies demonstrated the presence of clonal hematopoiesis as given myeloid malignancies-associated mutations such as TET2 and DNMT3A. In this study, I have unveiled molecular mechanisms of how accumulation of epigenetic alterations and genetic mutations including EZH2 promote the development of MDS and hematological malignancies by utilizing Ezh2 conditional knockout mice. In addition, I have provided a basis for specific rational epigenetic therapy for myeloid malignancies with Ezh2 dysfunction.

Research Products

• [Int'l Joint Research] Inner Mongolia University(China)
• [Journal Article] Multifaceted role of the polycomb-group gene EZH2 in hematological malignancies (2017)
  • Author(s): Sashida G, Iwama A
  • Journal Title: Int J Hematol Volume: 105 Issue: 1 Pages: 23-30
  • DOI: 10.1007/s12185-016-2124-x
  • Peer Reviewed
• [Journal Article] The loss of Ezh2 cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition. (2016)
  • Author(s): Sashida G, Wang S, Tomioka T, Oshima M, Kazumasa Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, Iwama A.
  • Journal Title: J Experimenta l Medicine Volume: 213 Issue: 8 Pages: 1459-1477
  • DOI: 10.1084/jem.20151121
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impact of combinatorial dysfunctions of Tet2 and Ezh2 on the epigenome in the pathogenesis of myelodysplastic syndrome. (2016)
  • Author(s): Hasegawa N, Oshima M, Sashida G, Matsui H, Koide S, Saraya A, Wang C, Muto T, Takane K, Kaneda A, Shimoda K, Nakaseko C, Yokote K, Iwama A.
  • Journal Title: Leukemia Volume: in press Issue: 4 Pages: 861-871
  • DOI: 10.1038/leu.2016.268
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. (2015)
  • Author(s): Mochizuki-Kashio M, Aoyama K, Sashida G, Oshima M, Tomioka T, Muto T, Wang C, Iwama A.
  • Journal Title: Blood Volume: 126 Issue: 10 Pages: 1172-83
  • DOI: 10.1182/blood-2015-03-634428
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Hidaka T, Kubuki Y, Sashida G, Aoyama K, Yoshimitsu M, Abe H, Miike T, Iwakiri H, Tahara Y, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K
  • Journal Title: Genom Data. Volume: 4 Pages: 102-108
  • DOI: 10.1016/j.gdata.2015.04.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Taniguchi Y, Hidaka T, Kubuki Y, Shimoda H, Marutsuka K, Sashida G, Aoyama K, Yoshimitsu M, Harada T, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K.
  • Journal Title: Blood Volume: 125 Issue: 2 Pages: 304-315
  • DOI: 10.1182/blood-2014-04-555508
  • NAID: 40020613861
  • Peer Reviewed / Open Access
• [Journal Article] Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice. (2015)
  • Author(s): Wang C, Oshima M, Sashida G, Tomioka T, Hasegawa N, Mochizuki-Kashio M, Nakajima-Takagi Y, Kusunoki Y, Kyoizumi S, Imai K, Nakachi K, Iwama A.
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0132041-e0132041
  • DOI: 10.1371/journal.pone.0132041
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Myelodysplastic syndrome with extramedullary erythroid hyperplasia induced by loss of Tet2 in mice. (2015)
  • Author(s): Muto T, Sashida G, Hasegawa N, Nakaseko C, Yokote K, Shimoda K, Iwama A.
  • Journal Title: Leuk Lymphoma. Volume: 56 Issue: 2 Pages: 520-523
  • DOI: 10.3109/10428194.2014.924120
  • 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] 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: Leukemia and Lymphoma Volume: 17 Issue: 21 Pages: 1-4
  • DOI: 10.1182/blood-2013-12-544544
  • Peer Reviewed
• [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: Nature Communications Volume: 18 Issue: 1 Pages: 5872-5882
  • DOI: 10.1038/ncomms6872
  • Peer Reviewed / Open Access
• [Presentation] Ezh2 loss promotes the transformation of ETP-ALL via suppressing T-cell differentiation regulators (2016)
  • Author(s): Sashida G, Wang C, Sato D, Oshima M, Matsui H, Nakajima-Takagi Y, Mochizuki-Kashio M, Iwama A
  • Organizer: 日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] The loss of Ezh2 cooperates with an active JAK2 mutant in the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition (2016)
  • Author(s): Sashida G, Wang C, Oshima M, Aoyama K, Kanai A, Mochizuki-Kashio M, Harada H, Shimoda K, Iwama A
  • Organizer: International Society for Experimental Hematology
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-08-25
  • Int'l Joint Research
• [Presentation] Ezh2 Loss Promotes the Transformation of Early T Cell Precursor Leukemia Via Suppressing Critical Genes for T-Cell Differentiation (2015)
  • Author(s): Goro Sashida, Changshan Wang, Daisuke Sato, Motohiko Oshima, Atsushi Iwama
  • Organizer: アメリカ血液学会年次総会
  • Place of Presentation: 米国オーランド
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Ezh2 loss accelerates JAK2V617F-driven primary myelofibrosis (2014)
  • Author(s): Sashida G, Tomioka T, Wang C, Shide K, Shimoda K, Iwama A.
  • Organizer: 日本血液学会総会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02