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Analysis of hematopoietic stem cell regulation by numerical chromosome anomaly and the mechanism of MDS pathogenesis

Research Project

Project/Area Number 21K19512
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
Research InstitutionKumamoto University

Principal Investigator

Sashida Goro  熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)

Project Period (FY) 2021-07-09 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywordsトリソミー8 / 造血幹細胞 / 骨髄異形成症候群 / クロマチン / 数的染色体異常 / 白血病 / トリソミー8 / クローン造血
Outline of Research at the Start

骨髄異形成症候群(MDS)は、造血幹細胞より発生する予後不良ながんである。MDSにおいて、トリソミー8などの数的染色体異常は、その予後と密接に関連しており、診断・治療法選択のための重要な判断基準でもある。しかし、その病態基盤は8番染色体上の責任領域・遺伝子を含めて、MDS細胞のゲノム変異・遺伝子発現変動のみの解析では、MDS幹細胞の不均一性もあり明白ではなかった。代表研究者は、人工染色体技術によりヒト8番染色体をマウスES細胞に新たに導入し、+8キメラマウスの作製に成功した。この世界にも類を見ないトリソミー8生体モデルを用いて、トリソミー8による造血幹細胞制御とMDS発症の機序を解明する。

Outline of Final Research Achievements

Myelodysplastic syndrome (MDS) is a poor prognosis cancer predominantly affecting the elderly that arises from hematopoietic stem cells, leads to hematopoietic failure, and partially transforms into acute myelogenous leukemia. Although it has long been known that numerical chromosome aberrations are involved in the pathogenesis of MDS, the pathogenetic basis of MDS remains unclear. In this study, we generated trisomy 8 chimeric mice, which are unique in the world, and analyzed the pathological basis of MDS development from the viewpoint of chromatin dysregulation. The self-renewal capacity of Trisomy 8 stem cells was reduced compared to the wild type, and their differentiation ability was impaired but not sufficient for MDS development; introduction of a mutation in the RUNX1 gene confirmed the development of MDS in cooperation with Trisomy 8.

Academic Significance and Societal Importance of the Research Achievements

トリソミー8に限らず、ダウン症を含めたトリソミーによって、年齢依存的にMDSや急性白血病が発症するが、余剰染色体の遺伝子発現だけから、がん化と白血病幹細胞発生の機序や、MDSで観察される全身性炎症の原因は説明できていない。本研究において、トリソミー8造血幹細胞のオミックス解析を実施したところ、トリソミー以外の染色体上の遺伝子発現異常、炎症応答の亢進やクロマチン構造制御の異常が確認できた。今後の解析によって、MDSの病態基盤の理解が進むとともに、新たな標的治療法の開発への進展が期待できる。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (9 results)

All 2023 2022 2021 Other

All Int'l Joint Research (2 results) Journal Article (4 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (3 results) (of which Invited: 2 results)

  • [Int'l Joint Research] Cancer Science Institute of Singapore(シンガポール)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] シンガポール国立大学(シンガポール)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs2023

    • Author(s)
      Yokomizo-Nakano T, Hamashima A, Kubota S, Bai J, Sorin S, Sun Y, Kikuchi K, Iimori M, Morii M, Kanai A, Iwama A, Huang G, Kurotaki D, Takizawa H, Matsui H, Sashida G.
    • Journal Title

      Journal of Experimental Medicine (JEM)

      Volume: 220 (7) Issue: 7 Pages: 9999-9999

    • DOI

      10.1084/jem.20220962

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The acidic domain of Hmga2 and the domain's linker region are critical for driving self-renewal of hematopoietic stem cell.2022

    • Author(s)
      Sun Y, Kubota S, Iimori M, Hamashima A, Murakami H, Bai J, Morii M, Yokomizo-Nakano T, Osato M, Araki K, Sashida G.
    • Journal Title

      Int J Hematol.

      Volume: 115 Issue: 4 Pages: 553-562

    • DOI

      10.1007/s12185-021-03274-9

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] RUNX1-ETO (RUNX1-RUNX1T1) induces myeloid leukemia in mice in an age-dependent manner2021

    • Author(s)
      Abdallah Mohamed Gaber、Niibori-Nambu Akiko、Morii Mariko、Yokomizo Takako、Yokomizo Tomomasa, at al.
    • Journal Title

      Leukemia

      Volume: 35 Issue: 10 Pages: 2983-2988

    • DOI

      10.1038/s41375-021-01268-4

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Overexpression of Hmga2 activates Igf2bp2 and remodels transcriptional program of Tet2-deficient stem cells in myeloid transformation2021

    • Author(s)
      Bai Jie、Yokomizo-Nakano Takako、Kubota Sho、Sun Yuqi、Kanai Akinori、Iimori Mihoko、Harada Hironori、Iwama Atsushi、Sashida Goro
    • Journal Title

      Oncogene

      Volume: 40 Issue: 8 Pages: 1531-1541

    • DOI

      10.1038/s41388-020-01629-w

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Earlier infection stresses and a driver genetic mutation facilitate myeloid transformation2021

    • Author(s)
      Goro Sashida
    • Organizer
      第94回生化学会大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Genetics/epigenetics-mediated enhancer activation in myeloid transformation.2021

    • Author(s)
      Goro Sashida
    • Organizer
      80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Understanding of Trisomy 8 hematopoietic stem cell function and transformation by generating a new Trisomy 8 model.2021

    • Author(s)
      Jie Bai, Kimi Araki, Sho Kubota, Takako Yokomizo-Nakano, Minetaro Ogawa, Narumi Uno, Yasuhiro Kazuki, Mitsuo Oshimura, Goro Sashida
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report

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Published: 2021-07-13   Modified: 2024-01-30  

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