Exploring the mechanism of mutation acquisition to induce tumorigenesis using Down syndrome associated leukemia model

• Project/Area Number: 19K17358
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kyoto University
• Principal Investigator: Nishinaka-Arai Yoko 京都大学, 医学研究科, 助教 (80789644)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 一過性骨髄異常増殖症 / 発がん / 多段階発がん / ダウン症候群 / 白血病

Outline of Research at the Start

一過性骨髄異常増殖症(TAM)は、ダウン症候群患児の生下時に合併する前白血病疾患である。TAM患者のうち約20%は一度寛解を経た後、追加変異を獲得し、急性巨核芽球性白血病(AMKL)へと進展することが知られている。このtrisomy21を背景にGATA1変異が生じた際に発症する前がん状態を経て、さらなる追加の遺伝子変異を獲得した際に真のがんへと病態進展する経緯は、多段階発がんモデルと考えられている。
本研究では、この TAM/AMKLモデルを用いて、多段階発がんとしての白血病発症に繋がる遺伝子変異の獲得のメカニズムを解明することを目標としている。

Outline of Final Research Achievements

Gene mutation acquisition mechanism which induced tumorigenesis was analyzed using the disease model applicable to the multi-step tumorigenesis theory.
We performed experiments that pluripotent stem cell pairs of disomy 21 (d21) and trisomy 21 (t21) clones were used and compared at each hematopoietic differentiation stage.
As a result, in the process of mutation acquisition and DNA damage repair, no significant difference was observed between d21 and t21 clones until early hematopoietic progenitor cells. On the other hand, the cell proliferation activity was not significantly different at the undifferentiated stage, but in hematopoietic progenitor cell stage, there was a tendency for increased cell cycle in t21 clones.

Academic Significance and Societal Importance of the Research Achievements

がんは日本人の死因第1位として知られており、その発生・進展は、ゲノム変異の蓄積によるクローン進化を基本原理とする、いわゆる多段階発がん説によって説明される。本研究は、多段階発がんのモデルとして知られるダウン症に合併する白血病に着目し、疾患特異的iPS細胞を用いて、その発症メカニズムを解析したものである。特色としては、細胞が遺伝子変異を獲得する流れを3段階に分けて定義することで、解析を可能としたことにあり、この定義は今回の対象疾患に留まらず、他のがん解析にも応用出来るものであると考えられる。

Research Products

• [Journal Article] Down syndrome-related transient abnormal myelopoiesis is attributed to a specific erythro-megakaryocytic subpopulation with GATA1 mutation. (2021)
  • Author(s): Nishinaka-Arai Y, Niwa A, Matsuo S, Kazuki Y, Yakura Y, Hiroma T, Toki T, Sakuma T, Yamamoto T, Ito E, Oshimura M, Nakahata T, Saito MK.
  • Journal Title: Haematologica Volume: 106(2) Issue: 2 Pages: 635-640
  • DOI: 10.3324/haematol.2019.242693
  • Peer Reviewed / Open Access
• [Journal Article] Pluripotent stem cell model of early hematopoiesis in Down syndrome reveals quantitative effects of short-form GATA1 protein on lineage specification. (2021)
  • Author(s): Matsuo S, Nishinaka-Arai Y, Kazuki Y, Oshimura M, Nakahata T, Niwa A, Saito MK.
  • Journal Title: PLoS One Volume: 16 (3) Issue: 3 Pages: e0247595-e0247595
  • DOI: 10.1371/journal.pone.0247595
  • Peer Reviewed / Open Access
• [Presentation] Down syndrome-related transient abnormal myelopoiesis is derived from a newly identified hematopoietic subpopulation (2019)
  • Author(s): Yoko Nishinaka-Arai, Akira Niwa, Shiori Matsuo, Yasuhiro Kazuki, Yuwna Yakura, Takehiro Hiroma, Tsutomu Toki, Tetsushi Sakuma, Takashi Yamamoto, Etsuro Ito, Mitsuo Oshimura, Tatsutoshi Nakahata, and Megumu K. Saito
  • Organizer: ISSCR 2019 annual meeting
  • Int'l Joint Research
• [Presentation] hPSC model reveals impact of GATA1 mutation on a newly defined subpopulation leading to TAM (2019)
  • Author(s): Yoko Nishinaka-Arai, Akira Niwa, Shiori Matsuo, Yasuhiro Kazuki, Yuwna Yakura, Takehiro Hiroma, Tsutomu Toki, Tetsushi Sakuma, Takashi Yamamoto, Etsuro Ito, Mitsuo Oshimura, Tatsutoshi Nakahata, and Megumu K. Saito
  • Organizer: 第81回日本血液学会学術集会