Roles for RUNX1/AML1 in DNA damage-repair pathway

• Project/Area Number: 23591385
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kobe Shoin Women's University (2012-2013); Osaka University (2011)
• Principal Investigator: SATOH Yusuke 神戸松蔭女子学院大学, 人間科学部, 准教授 (20506307)
• Co-Investigator(Kenkyū-buntansha): KANAKURA Yuzuru 大阪大学, 医学系研究科, 教授 (20177489) ; ORITANI Kenji 大阪大学, 医学系研究科, 教授 (70324762)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: RUNX1 / MDS / AML / DNA損傷 / 骨髄異形成症候群 / 造血幹細胞 / DNA修復

Research Abstract

We found that the C-terminal deletion mutant of RUNX1 attenuates DNA-damage repair responses in hematopoietic stem/progenitor cells. Bone marrow cells from MDS/AML patients harboring the RUNX1-C-terminal mutation showed significantly lower levels of GADD45A expression compared with those from MDS/AML patients with wild-type RUNX1. As for this mechanism, we found that RUNX1 directly regulates the transcription of GADD45A. These results suggest Gadd45a dysfunction due to RUNX1 mutations can cause additional mutation(s) required for multi-step leukemogenesis.

Research Products

• [Journal Article] Complementary regulation of early B-lymphoid differentiation by genetic and epigenetic mechanisms (2013)
  • Author(s): Yokota T, Sudo T, Ishibashi T, Doi Y, Ichii M, Orirani K, Kanakura Y
  • Journal Title: Int J Hematol Volume: 98 Pages: 382-389
  • Peer Reviewed
• [Journal Article] The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages (2013)
  • Author(s): Satoh Y, Yokota T, Sudo T, Kondo M, Lai A, Kincade PW, Kouro T, Iida R, Kokame K, Miyata T, Habuchi Y, Matsui K, Tanaka H, Matsumura I, Oritani K, Kohwi-Shigematsu T, Kanakura Y
  • Journal Title: Immunity Volume: 38 Pages: 1105-1115
  • Peer Reviewed
• [Journal Article] The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. (2013)
  • Author(s): Satoh Y, Yokota T, Sudo T, Kondo M, Lai A, Kincade PW, Kouro T, Iida R, Kokame K, Miyata T, Habuchi Y, Matsui K, Tanaka H, Matsumura I, Oritani K, Kohwi-Shigematsu T, Kanakura Y.
  • Journal Title: Immunity Volume: 38 Issue: 6 Pages: 1105-1115
  • DOI: 10.1016/j.immuni.2013.05.014
  • Peer Reviewed
• [Journal Article] The endothelial antigen ESAM monitors hematopoietic stem cell status between quiescence and selfrenewal (2012)
  • Author(s): Sudo T, Yokota T, Oritani K, Satoh Y, Sugiyama T, Ishida T, Shibayama H, Ezoe S, Fujita N, Tanaka H, Maeda T, Nagasawa T, Kanakura Y
  • Journal Title: Journal of Immunology Volume: 189 Pages: 200-210
  • Peer Reviewed
• [Journal Article] C- terminal mutation of RUNX1 attenuates the DNA- damage repair response in hematopoietic stem cells (2012)
  • Author(s): Satoh Y, Matsumura I, Tanaka H, Harada H, Harada Y, Matsui K, Shibata M, Mizuki M, Kanakura Y
  • Journal Title: Leukemia Volume: 26 Pages: 303-311
  • Peer Reviewed
• [Journal Article] NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells (2012)
  • Author(s): Matsui K, Ezoe S, Oritani K, Shibata M, Tokunaga M, Fujita N, Tanimura A, Sudo T, Tanaka H, McBurney MW, Matsumura I, Kanakura Y
  • Journal Title: Biochem Biophys Res Commun Volume: 418 Pages: 811-817
  • Peer Reviewed
• [Journal Article] The Endothelial Antigen ESAM Monitors Hematopoietic Stem Cell Status between Quiescence and Self-Renewal. (2012)
  • Author(s): Sudo, T.
  • Journal Title: J. Immunol. Volume: 189 Issue: 1 Pages: 200-210
  • DOI: 10.4049/jimmunol.1200056
  • Peer Reviewed
• [Journal Article] C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells (2012)
  • Author(s): Satoh Y, Mizuki M, Kanakura Y, et al
  • Journal Title: Leukemia Volume: 26(2) Issue: 2 Pages: 303-311
  • DOI: 10.1038/leu.2011.202
  • Peer Reviewed
• [Journal Article] Myeloid neoplasm- related gene abnormalities differentially affect dendritic cell differentiation from murine hematopoietic stem/progenitor cells (2011)
  • Author(s): Fujita J, Mizuki M, Otsuka M, Ezoe S, Tanaka H, Satoh Y, Fukushima K, Tokunaga M, Matsumura I, Kanakura Y
  • Journal Title: Immunol Lett Volume: 136 Pages: 61-73
  • Peer Reviewed
• [Journal Article] Myeloid neoplasm-related gene abnormalities differentially affect dendritic cell differentiation from murine hematopoietic stem/progenitor cells. (2011)
  • Author(s): Fujita J, Mizuki M, Otsuka M, Ezoe S, Tanaka H, Satoh Y, Fukushima K, Tokunaga M, Matsumura I, Kanakura Y.
  • Journal Title: Immunol Lett. Volume: 136 Pages: 61-73
  • Peer Reviewed
• [Presentation] Endothelial Cell-Selective Adhesion Molecule Marks Human Hematopoietic Stem Cells Regardless Of The HSC Sources (2013)
  • Author(s): Ishibashi T, Yokota T, Ichii M, Satoh Y, Sudo T, Doi Y, Fujita N, Nagate Y, Hamanaka Y, Matsui K, Tanimura A, Saitoh N, Ezoe S, Shibayama H, Kincade PW, Oritani K, Kanakura Y
  • Organizer: The American Society of Hematology 55th Annual Meeting
  • Place of Presentation: ニューオリンズ
  • Year and Date: 2013-12-08
• [Presentation] Endothelial Cell-Selective Adhesion Molecule Marks Human Hematopoietic Stem Cells Regardless Of The HSC Sources (2013)
  • Author(s): Ishibashi T, Yokota T, Ichii M, Satoh Y, Sudo T, Doi Y, Fujita N, Nagate Y, Hamanaka Y, Matsui K, Tanimura A, Saitoh N, Ezoe S, Shibayama H, Kincade PW, Oritani K, Kanakura Y
  • Organizer: 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans
• [Presentation] An Anti-Apoptotic Molecule, Anamorsin, Is Essential for Erythropoiesis Through the Regulation of Cellular Labile Iron Pool (2012)
  • Author(s): Tanimura A, Hamanaka Y, Fujita N, Doi Y,Ishibashi T, Sudo T, Matsui K, Ichii M, Saitoh N, Satoh Y, Ezoe S, Yokota T, Oritani K, Shibayama H, Kanakura Y
  • Organizer: The American Society of Hematology 54th Annual Meeting
  • Place of Presentation: アトランタ
  • Year and Date: 2012-12-10
• [Presentation] Satb1 promotes hematopoietic stem cell differentiation toward the lymphoid lineages (2011)
  • Author(s): Satoh Y, Yokota T, Kondo M, Lai A, Kincade P, Kouro T, Iida R, Kokame K, Miyata T, Sudo T, Tanaka H, Matsumura I, Oritani K, Kohwi-Shigematsu T, Kanakura Y
  • Organizer: The American Society of Hematology 53rd Annual Meeting
  • Place of Presentation: サンディエゴ
  • Year and Date: 2011-12-12
• [Presentation] SATB1 Induces Early Lymphocyte Differentiation From Primitive Hematopoietic Progenitors (2011)
  • Author(s): Satoh Y, Yokota T, Tanaka H, Kokame K, Miyata T, Matsumura I, Oritani K, Kanakura Y
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場(名古屋)
  • Year and Date: 2011-10-15
• [Presentation] RUNX1 C- terminal Mutation Attenuates The DNA- damage Repair Response in Hematopoietic Stem/Progenitor Cells (2011)
  • Author(s): Satoh Y, Matsumura I, Tanaka H, Kanakura Y
  • Organizer: JSH International Symposium 2011 in Nagasaki
  • Place of Presentation: 長崎ブリックホール(長崎)
  • Year and Date: 2011-04-23
• [Presentation] RUNX1 C-terminal Mutation Attenuates The DNA-damage Repair Response in Hematopoietic Stem/Progenitor Cells. (2011)
  • Author(s): Satoh Y, Matsumura I, Tanaka H, Kanakura Y
  • Organizer: JSH International Symposium 2011 in Nagasaki
  • Place of Presentation: 長崎ブリックホール（長崎）
• [Presentation] SATB1 Induces Early Lymphocyte Differentiation From Primitive Hematopoietic Progenitors. (2011)
  • Author(s): Satoh Y, Yokota T, Tanaka H, Kokame K, Miyata T, Matsumura I, Oritani K, Kanakura Y
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場（名古屋）
• [Presentation] Satb1 promotes hematopoietic stem cell differentiation toward the lymphoid lineages. (2011)
  • Author(s): Satoh Y, Yokota T, Kondo M, Lai A, Kincade P, Kouro T, Iida R, Kokame K, Miyata T, Sudo T, Tanaka H, Matsumura I, Oritani K, Kohwi-Shigematsu T, Kanakura Y.
  • Organizer: The American Society of Hematology 53rd Annual Meeting
  • Place of Presentation: San Diego convention center (San Diego, USA)
• [Presentation] An Anti-Apoptotic Molecule, Anamorsin, Is Essential for Erythropoiesis Through the Regulation of Cellular Labile Iron Pool
  • Author(s): Tanimura A, Hamanaka Y, Fujita N, Doi Y, Ishibashi T, Sudo T, Matsui K, Ichii M, Saitoh N, Satoh Y, Ezoe S, Yokota T, Oritani K, Shibayama H, Kanakura Y.
  • Organizer: The American Society of Hematology 54th Annual Meeting.
  • Place of Presentation: Georgia World Congress Center (Atlanta USA)