Role of polycomb histone methyltransferase EZH1 in hematologic malignances

• Project/Area Number: 16K19565
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Chiba University
• Principal Investigator: Aoyama Kazumasa 千葉大学, 大学院医学研究院, 特任助教 (50734266)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: エピジェネティック制御 / 癌 / 遺伝子発現制御 / ポリコーム / 造血器腫瘍 / 発現制御

Outline of Final Research Achievements

Ezh1 and 2 repress gene expression by catalyzing trimethylation at histone H3 lysine 27 (H3K27me3). Here, we examined Ezh1+/-Ezh2Δ/Δ mice. ChIP sequence analysis revealed that a cohort of PRC2 targets marked with higher levels of H3K27me3 than the other targets in hematopoietic stem and progenitor cells (HSPCs), retained high levels of H3K27me3 in Ezh1+/-Ezh2Δ/Δ HSPCs. Moreover, using SKM-1 cells, derived from human MDS patients with EZH2 mutant, we showed that repression of core PRC2 targets is critical for the maintenance of human PRC2-insufficient MDS.

Research Products

• [Journal Article] Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies (2017)
  • Author(s): Tanaka Tomoyuki、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Tara Shiro、Oshima Motohiko、Saraya Atsunori、Koide Shuhei、Si Sha、Manabe Ichiro、Sanada Masashi、Nakayama Manabu、Masuko Masayoshi、Sone Hirohito、Koseki Haruhiko、Iwama Atsushi
  • Journal Title: The Journal of Experimental Medicine Volume: 214 Issue: 10 Pages: 2901-2913
  • DOI: 10.1084/jem.20170167
  • Peer Reviewed / Open Access
• [Journal Article] Hmga2 collaborates with JAK2 V617F in the development of myeloproliferative neoplasms (2017)
  • Author(s): Ueda K, Ikeda K, Ikezoe T, Harada-Shirado K, Ogawa K, Hashimoto Y, Sano T, Ohkawara H, Kimura S, Shichishima-Nakamura A, Nakamura Y, Shikama Y, Mori T, Mason PJ, Bessler M, Morishita S, Komatsu N, Shide K, Shimoda K, Koide S, Aoyama K, Oshima M, Iwama Aand Takeishi Y.
  • Journal Title: Blood Advances Volume: 1 Issue: 15 Pages: 1001-1015
  • DOI: 10.1182/bloodadvances.2017004457
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancement of TGF-β-induced Smad3 activity by c-Abl-mediated tyrosine phosphorylation of its coactivator SKI-interacting protein (SKIP). (2017)
  • Author(s): Kuki K, Yamaguchi N, Iwasawa S, Takakura Y, Aoyama K, Yuki R, Nakayama Y, Kuga T, Hashimoto Y, Tomonaga T, Yamaguchi N
  • Journal Title: Biochemical and biophysical research communications Volume: 490 Issue: 3 Pages: 1045-1051
  • DOI: 10.1016/j.bbrc.2017.06.163
  • Peer Reviewed / Open Access
• [Journal Article] Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition. (2017)
  • Author(s): Ola Rizq, Naoya Mimura, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Yuko Kato, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Changshan Wang, Tetsuhiro Chiba, Anqi Ma, Jian Jin, Tohru Iseki, Chiaki Nakaseko, and Atsushi Iwama
  • Journal Title: Clinical Cancer Research Volume: 23(16) Issue: 16 Pages: 4817-4830
  • DOI: 10.1158/1078-0432.ccr-16-2735
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Protective role for lipid modifications of Src-family kinases against chromosome missegregation (2016)
  • Author(s): Honda, T., Soeda, S., Tsuda, K., Yamaguchi, C., Aoyama, K., Morinaga, T., Yuki, R., Nakayama, Y., Yamaguchi, N.-t., and Yamaguchi, N.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 38751-38751
  • DOI: 10.1038/srep38751
  • Peer Reviewed / Open Access
• [Journal Article] Possible role of intragenic DNA hypermethylation in gene silencing of the tumor suppressor gene NR4A3 in acute myeloid leukemia. (2016)
  • Author(s): Shimizu R, Muto T, Aoyama K, Choi K, Takeuchi M, Koide S, Hasegawa N, Isshiki Y, Togasaki E, Kawajiri-Manako C, Nagao Y, Tsukamoto S, Sakai S, Takeda Y, Mimura N, Ohwada C, Sakaida E, Iseki T, Starczynowski DT, Iwama A, Yokote K, Nakaseko C.
  • Journal Title: Leuk Res. Volume: 50 Pages: 85-94
  • DOI: 10.1016/j.leukres.2016.09.018
  • 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] Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of non-hematopoietic genes. (2016)
  • Author(s): Koide S, Oshima M, Takubo K, Yamazaki S, Nitta E, Saraya A, Aoyama K, Kato Y, Miyagi S, Nakajima-Takagi Y, Chiba T, Matsui H, Arai F, Suzuki Y, Kimura H, Nakauchi H, Suda T, Shinkai Y,Iwama A.
  • Journal Title: Blood Volume: 128(5) Issue: 5 Pages: 638-649
  • DOI: 10.1182/blood-2016-01-694810
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Pcgf5 Affects Global H2A Monoubiquitination but Not the Function of Hematopoietic Stem and Progenitor Cells (2016)
  • Author(s): Si S, Nakajima-Takagi Y, Aoyama K, Oshima M, Saraya A, Sugishita H, Nakayama M, Ishikura T, Koseki H, Iwama A
  • Journal Title: PLoS One Volume: 11 Issue: 5 Pages: e0154561-e0154561
  • DOI: 10.1371/journal.pone.0154561
  • Peer Reviewed / Open Access
• [Presentation] Profiling of the critical targets of polycomb repressive complex 2 in the maintenance of myelodysplastic syndrome stem cells (2018)
  • Author(s): Kazumasa Aoyama, Emi Suzuki, Motohiko Oshima, Makiko Mochizuki-Kashio1, Shuhei Koide1, Yuko Kato, Yaeko Nakajima-Takagi, Goro Sashida, Atsushi Iwama
  • Organizer: Keystone Syposia, Cancer Epigenetics: New Mechanisms, New Therapies (B4)
  • Int'l Joint Research
• [Presentation] Ezh2 欠損造血幹細胞維持における Ezh1 によるエピジェネティック制御 (2017)
  • Author(s): 青山 和正, 鈴木 瑛美, 大島 基彦, 望月-樫尾 牧子, 小出 周平, 加藤 裕子, 中島 やえ子, 指田 吾郎, 岩間 厚志
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] Role of the polycomb methyltransferase Ezh1 in myelodysplastic syndrome induced by Ezh2 insufficiency (2016)
  • Author(s): Kazumasa Aoyama, Makiko Mochizuki-Kashio, Motohiko Oshima, Shuhei Koide, Yaeko Nakajima-Takagi, Mitsutaka Maeda, Goro Sashida, Atsushi Iwama
  • Organizer: 58th American Society of Hematology (ASH) Annual Meeting
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Ezh2 欠損造血細胞における Ezh1 によるエピジェネティック制御 (2016)
  • Author(s): 青山 和正, 望月-樫尾 牧子, 大島 基彦, 小出 周平, 中島 やえ子, 指田 吾郎, 岩間 厚志
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター、東北大学川内北キャンパス (宮城県仙台市）
  • Year and Date: 2016-09-25