Analysis of pathogenic mechanisms of myelodysplastic syndrome by deregulation of histone H3K27

• Project/Area Number: 26293227
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Hiroshima University
• Principal Investigator: Honda Hiroaki 広島大学, 原爆放射線医科学研究所, 教授 (40245064)
• Co-Investigator(Kenkyū-buntansha): 上田 健 広島大学, 原爆放射線医科学研究所, 助教 (60585149) ; 本田 善一郎 お茶の水女子大学, 保健管理センター, 教授 (70238814) ; 稲葉 俊哉 広島大学, 原爆放射線医科学研究所, 教授 (60281292)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: ヒストン修飾 / ポリコーム複合体 / EED / コンディショナルノックアウトマウス / 骨髄異形成症候群 / 白血病 / ヒストンメチル化・脱メチル化 / ヒストンH3K27 / PRC2 / JMJD3, UTX / Jmjd3, Utx / ヒストンH3K27メチル化

Outline of Final Research Achievements

EED is a component of polycomb repressive complex 2 and is found to be mutated in samples of myelodysplastic syndrome (MDS). We generated conditional heterozygous mice for Eed (Eed+/Δ) and found that Eed+/Δ mice exhibited hematopoietic abnormalities resembling MDS. In addition, in a competitive repopulation assay, Eed+/Δ hematopoietic stem cells (HSCs) showed higher chimerism than control HSCs, and by retrovirus-mediated insertional mutagenesis, Eed+/Δ mice exhibited higher incidence of leukemia than control mice. These results indicate that heterozygosity of Eed induced MDS and rendered high susceptibility to leukemia by enhancing proliferative activity of HSCs.

Research Products

• [Int'l Joint Research] National Institute of Health(米国)
• [Journal Article] Propagation of tri-methylated H3K27 regulated by EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression. (2016)
  • Author(s): Ueda T, Nakata Y, Nagamachi A, Yamasaki N, Kanai A, Matsui H, Honda ZI, Oda H, Wolff L, Inaba T, Honda H.
  • Journal Title: PNAS Volume: 113(37) Issue: 37 Pages: 10370-10375
  • DOI: 10.1073/pnas.1600070113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency (2016)
  • Author(s): Ikeda K-I, Ueda T, Yamasaki N, Nakata Y, Sera Y, Nagamachi A, Miyama T, Kobayashi H, TakuboK, Kanai A, Oda H, Wolff l, Honda Z-1, Ichinohe T, Matsubara A, Suda T, Inaba T, Honda H
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 29454-29454
  • DOI: 10.1038/srep29454
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia. (2016)
  • Author(s): Sera Y, Yamasaki N, Oda H, Nagamachi A, Wolff L, Inukai T, Inaba T, Honda H.
  • Journal Title: Cancer Sci Volume: 107 Issue: 7 Pages: 890-898
  • DOI: 10.1111/cas.12945
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ALKR1275Q perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN. (2016)
  • Author(s): Ueda T, Nakata Y, Yamasaki N, Oda H, Sentani K, Kanai A, Onishi N, Ikeda K, Sera Y, Honda ZI, Tanaka K, Sata M, Ogawa S, Yasui W, Saya H, Takita J, Honda H.
  • Journal Title: Oncogene. Volume: 無 Issue: 34 Pages: 4447-4458
  • DOI: 10.1038/onc.2015.519
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fbxl10 overexpression in murine hematopoietic stemcells induces leukemia involving metabolic activation and upregulation of Nsg2 (2015)
  • Author(s): Ueda T, Nagamachi A, Takubo K, Yamasaki N, Matsui H, Kanai A, Nakata Y, Ikeda K Konuma T, Oda H, Wolff L, Honda Z, Wu X, Helin K, Iwama A, Suda T, Inaba T, Honda H.
  • Journal Title: Blood Volume: 125 Issue: 22 Pages: 3437-3446
  • DOI: 10.1182/blood-2014-03-562694
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation. (2015)
  • Author(s): Wada T, Koyama D, Kikuchi J, Honda H, Furukawa Y.
  • Journal Title: Blood Volume: 125 Issue: 24 Pages: 3731-3746
  • DOI: 10.1182/blood-2014-11-610907
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] -7/7q- syndrome in myeloid-lineage hematopoietic malignancies: attempts to understand this complex disease entity. (2015)
  • Author(s): Honda H, Nagamachi A, Inaba T.
  • Journal Title: Oncogene Volume: 34 Issue: 19 Pages: 2413-2425
  • DOI: 10.1038/onc.2014.196
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Jmjd3コンディショナルノックインマウスにおける白血病感受性亢進機構の解析 (2016)
  • Author(s): 池田健一郎、上田健、長町安希子、山崎憲政、中田雄一郎、世良康如、小畠浩平、稲葉俊哉、本田浩章
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Analysis of pathogenic mechanisms and development of therapeutic approaches using mouse cancer models (2016)
  • Author(s): Hiroaki Honda
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] AMLの分子機構 (2016)
  • Author(s): 本田浩章
  • Organizer: 第78回日本血液学学会総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] Functional analysis of UTX, a histone demethylase for H3K27, in normal hematopoiesis and hematologic malignancies (2015)
  • Author(s): Yasuyuki Sera, Takeshi Ueda, Yuichiro Nakata, Ken-ichiro Ikeda, Norimasa Yamasaki, Hideaki Oda, Zen-ichiro Honda and Hiroaki Honda
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kanazawa
  • Year and Date: 2015-10-16
• [Presentation] Haploinsufficiency of Eed enhances to tumor susceptibility and develop leukemia with overexpression of Evi1 (2015)
  • Author(s): Kenichiro Ikeda, Takeshi Ueda, Akiko Nagamachi, Norimasa Yamasaki, Yuichiro Nakata, Toshiya Inaba, Hiroaki Honda
  • Organizer: The 74th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
  • Year and Date: 2015-09-29
• [Presentation] Analysis of leukemogenic mechanisms by deregulated methylation of histone H3K27 (2014)
  • Author(s): Honda H
  • Organizer: The 73rd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Tokyo
  • Year and Date: 2014-09-27
  • Invited
• [Remarks] 広島大学・疾患モデル解析研究分野
  • URL: http://home.hiroshima-u.ac.jp/sosai/top.html
• [Remarks] 広島大学原爆放射線医科学研究所・疾患モデル解析研究分野HP
  • URL: http://home.hiroshima-u.ac.jp/sosai/top.html