Role of EED mutation in hematologic malignancy

• Project/Area Number: 26460391
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kindai University (2016); Hiroshima University (2014-2015)
• Principal Investigator: UEDA Takeshi 近畿大学, 医学部, 講師 (60585149)
• Co-Investigator(Kenkyū-buntansha): 本田 浩章 広島大学, 原爆放射線医科学研究所, 教授 (40245064)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: エピジェネティクス

Outline of Final Research Achievements

EED acts as a non-catalytic component of polycomb repressive complex 2 (PRC2) that is a central regulator of histone H3 Lys27 (H3K27) methylation associated with transcriptional repression. We previously identified EED Ile363Met (I363M) mutation in myelodysplastic syndrome and related diseases. In this study, to investigate the role of I363M in disease pathogenesis, we generated and analyzed EED I363M knock-in mice. As a result, the I363M mutation was shown to inhibit the propagation of trimethylated H3K27 repressive marks in vivo. In addition, we demonstrated that the heterozygotes enhanced hematopoietic stem/progenitor cell activity and contributed to increased susceptibility to leukemia, while the homozygotes resulted in embryonic lethality.

Research Products

• [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] 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] Fbxl10 overexpression in murine hematopoietic stem cells 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
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] EED変異体によるPRC2活性化障害の造血器腫瘍発症における役割 (2016)
  • Author(s): 上田健、中田雄一郎、長町安希子、山崎憲政、金井昭教、松井啓隆、稲葉俊哉、本田浩章
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター (宮城)
  • Year and Date: 2016-09-25
• [Presentation] ヒストン脱メチル化酵素Fbxl10の白血病発症における機能解析 (2016)
  • Author(s): 上田健、池田健一郎
  • Organizer: 第20回日本がん分子標的治療学会
  • Place of Presentation: 別府国際コンベンションセンター (大分)
  • Year and Date: 2016-05-31
• [Presentation] ヒストン脱メチル化酵素Fbxl10の白血病における機能解析 (2015)
  • Author(s): 上田 健、長町安希子、中田雄一郎、山崎憲政、稲葉俊哉、本田浩章
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学大会 合同大会 （ポスター)
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] Disease-associated EED Ile363Met mutation increases susceptibility to hematologic malignancies (2014)
  • Author(s): 上田 健, 長町安希子,中田雄一郎, 山崎憲政, 松井啓隆, 本田浩章
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-10-16