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Understanding of pathogenesis of Trisomy 8-induced myelodysplastic syndrome

Research Project

Project/Area Number 19K22640
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) 2019-06-28 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywordsトリソミー8 / 骨髄異形成症候群 / 数的染色体異常 / 造血幹細胞 / クロマチン / キメラマウス / トリソミー8 / エピゲノム / 転写因子 / クローン造血
Outline of Research at the Start

骨髄異形成症候群(MDS)は、高齢者に好発する予後不良ながんである。染色体異常による病態基盤を理解するために、疾患iPS細胞は-7/7q- MDSで報告されているが、元来、MDS細胞は増殖活性が低く、疾患iPS作製過程でMDS本来のエピゲノム病態も消失しており、発症機序の検証には適当ではない。また、ヒトMDS幹細胞は免疫不全マウスに長期間維持できず、異種移植による解析は極めて困難である。こうした病態研究の困難を打破するために、人工染色体とゲノム編集技術を融合したヒト8番染色体導入・マウス変異ES細胞による+8 MDSモデルを新たに確立することで、数的染色体異常によるMDS発症機構を解明する。

Outline of Final Research Achievements

It has long been known that chromosomal abnormalities are deeply involved in the development and progression of cancer. In myelodysplastic syndrome (MDS), numerical chromosomal abnormalities such as trisomy 8 and monosomy 7 are closely related to the pathophysiology and prognosis of MDS, and are also essential criteria for diagnosis and treatment selection. Although trisomy 8 has a relatively poor prognosis, the responsible gene and responsible region on chromosome 8 were not clarified due to the heterogeneity of MDS cells by examining only alteration of expression of genes in Chromosome 8. Under these circumstances, we introduced human chromosome 8 into mouse ES cells using artificial chromosome technology, created a +8 chimeric mouse, established a new MDS model, and analyzed the function of +8 hematopoietic stem cell.

Academic Significance and Societal Importance of the Research Achievements

数的染色体異常によるMDS発症機構の分子メカニズムは未だ明らかでない。本研究によって、こうしたMDSの病態基盤が解明されることで、病態に応じた治療法開発のための知見が期待できる。さらに、申請者の新規がん生体モデルによって、全く未知であった数的染色体異常によるがん発症機構の一端が理解できる。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (14 results)

All 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (8 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (4 results)

  • [Int'l Joint Research] シンシナティ小児病院/メモリアルスローンケタリングキャンサーセンター(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] National University of Singapore(シンガポール)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Two faces of RUNX3 in myeloid transformation2021

    • Author(s)
      Yokomizo-Nakano Takako、Sashida Goro
    • Journal Title

      Experimental Hematology

      Volume: 97 Pages: 14-20

    • DOI

      10.1016/j.exphem.2021.02.005

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [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
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Overexpression of RUNX3 Represses RUNX1 to Drive Transformation of Myelodysplastic Syndrome2020

    • Author(s)
      Yokomizo-Nakano Takako、Kubota Sho、Bai Jie、Hamashima Ai、Morii Mariko、Sun Yuqi、Katagiri Seiichiro、Iimori Mihoko、Kanai Akinori、Tanaka Daiki、Oshima Motohiko、Harada Yuka、Ohyashiki Kazuma、Iwama Atsushi、Harada Hironori、Osato Motomi、Sashida Goro
    • Journal Title

      Cancer Research

      Volume: 80 Issue: 12 Pages: 2523-2536

    • DOI

      10.1158/0008-5472.can-19-3167

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Low prevalence of the BCR-ABL1 fusion gene in a normal population in southern Sarawak.2020

    • Author(s)
      Kuan JW, Su AT, Tay SP, Fong IL, Kubota S, Su'ut L, Osato M, Sashida G.
    • Journal Title

      International Journal of Hematology

      Volume: 111 Issue: 2 Pages: 217-224

    • DOI

      10.1007/s12185-019-02768-x

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Deregulated Polycomb functions in myeloproliferative neoplasms.2019

    • Author(s)
      Sashida G, Oshima M, Iwama A.
    • Journal Title

      Int J Hematol

      Volume: 110 Issue: 2 Pages: 170-178

    • DOI

      10.1007/s12185-019-02600-6

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lineage-specific RUNX2 super-enhancer activates MYC via a chromosomal translocation and promotes the development of blastic plasmacytoid dendritic cell neoplasm2019

    • Author(s)
      Kubota S, Tokunaga K, Umezu T, Yokomizo-Nakano T, Oshima M, Tan KT, Yang H, Kanai A. Iwanaga E, Asou N, Maeda T, Nakagata N. Ito T, Iwama A. Ohyashiki K, Osato M, Sashida G.
    • Journal Title

      Nat Commun

      Volume: 10 Issue: 1 Pages: 1653-1653

    • DOI

      10.1038/s41467-019-09710-z

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] RUNX3 levels in human hematopoietic progenitors are regulated by aging and dictate erythroid-myeloid balance2019

    • Author(s)
      Balogh Peter、Adelman Emmalee R.、Pluvinage John V.、Capaldo Brian J.、Freeman Katie C.、Singh Sandeep、Elagib Kamaleldin E.、Nakamura Yukio、Kurita Ryo、Sashida Goro、Zunder Eli R.、Li Hui、Gru Alejandro A.、Price Elizabeth A.、Schrier Stanley L.、Weissman Irving L.、Figueroa Maria E.、Pang Wendy W.、Goldfarb Adam N.
    • Journal Title

      Haematologica

      Volume: 105 Issue: 4 Pages: 905-913

    • DOI

      10.3324/haematol.2018.208918

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Ascl1-induced Wnt11 regulates neuroendocrine differentiation, cell proliferation, and E-cadherin expression in small-cell lung cancer and Wnt11 regulates small-cell lung cancer biology2019

    • Author(s)
      Tenjin Yuki、Kudoh Shinji、Kubota Sho、Yamada Tatsuya、Matsuo Akira、Sato Younosuke、Ichimura Takaya、Kohrogi Hirotsugu、Sashida Goro、Sakagami Takuro、Ito Takaaki
    • Journal Title

      Laboratory Investigation

      Volume: 99 Issue: 11 Pages: 1622-1635

    • DOI

      10.1038/s41374-019-0277-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] RUNX3 over-expression impedes RUNX1 function and promotes the development of myelodysplastic syndrome2019

    • Author(s)
      Takako Yokomizo, Sho Kubota, Atsushi Iwama, Hironori Harada, Motomi Osato, Goro Sashida
    • Organizer
      日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Stress and aging impair the transcriptome of MLL-AF9 stem cells and impede the leukemic transformation2019

    • Author(s)
      Ayaka Maeda, Sho Kubota, Takako Yokomizo, Mihoko Iimori, Kimi Araki, Motomi Osato, Goro Sashida
    • Organizer
      日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Loss of Tif1b suppressed the development of BCR-ABL-induced leukemia2019

    • Author(s)
      Mariko Morii, Sho Kubota, Takako Yokomizo-Nakano, Masayoshi Tasaki, Kimi Araki, Goro Sashida
    • Organizer
      日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] HSCs-specific induction of Hmga2 ensures the enhanced self-renewal property2019

    • Author(s)
      Yuqi Sun, Sho Kubota, Jie Bai, Takako Yokomizo-Nakano, Mariko Morii, Kimi Araki, Motomi Osato, Goro Sashida
    • Organizer
      日本血液学会学術集会
    • Related Report
      2019 Research-status Report

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Published: 2019-07-04   Modified: 2022-01-27  

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