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Regulation of cancer specific chromatin and transcriptional network by Hmga2

Research Project

Project/Area Number 19K08842
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKumamoto University

Principal Investigator

Yokomizo Takako  熊本大学, 国際先端医学研究機構, 特定事業研究員 (40636867)

Co-Investigator(Kenkyū-buntansha) 白 潔  熊本大学, 国際先端医学研究機構, 外国人客員研究員 (60775336)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsHmga2 / 造血幹細胞 / MDS / エピゲノム / 白血病
Outline of Research at the Start

近年、健常高齢者において、骨髄異形成症候群(MDS)や慢性骨髄増殖性腫瘍(MPN)と同様に、エピゲノム制御遺伝子変異を持つクローナル造血・前がん状態が報告され、エピゲノム異常のがん発症過程における重要性が再認識されている。しかし、加齢幹細胞からがん幹細胞への形質転換とMDS・MPN発症に至る仕組みは明白ではない。本研究では、造血幹細胞特異的なHmga2発現を誘導できる新規マウスを活用して、エピゲノム制御機構の破綻を介した、HMGA2によるがん幹細胞の発生と病態進展の分子基盤を解明する。

Outline of Final Research Achievements

High Mobility Group AT-hook 2 (HMGA2) is a chromatin modifier and the expression levels of Hmga2 were found to be markedly higher in fetal HSCs than in adult HSCs. Furthermore, overexpression of Hmga2 has been found in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although Hmga2 had been known to enhance the self-renewal capacity of HSCs, the molecular mechanism of how Hmga2 regulates chromatin complexes of normal HSC and MDS-stem cells is still unclear. In this study, we showed Hmga2 directly activated Igf2bp2 to enhance the self-renew of HSC, but also repressed the inflammatory response to protect HSC from damage in the stress condition. Hmga2 may regulate transcriptional program to maintain normal hematopoiesis and regeneration in the response to environmental stress.

Academic Significance and Societal Importance of the Research Achievements

Hmga2は胎児造血幹細胞の高い自己複製機能に必須の因子であるほか、骨髄異形成症候群(MDS)や急性骨髄性白血病(AML)においてがん遺伝子としての機能も示唆されている。本研究では、成体造血においてHmga2がストレス状況下で造血幹細胞を障害から守り、造血の維持と再生に寄与するという新たなHmga2の機能を示した。本研究成果は、老化造血幹細胞の若返りや、がん幹細胞の維持機構を理解する上で意義深いものと考える。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (2 results)

All 2022 2021

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 1 results)

  • [Journal Article] The acidic domain of Hmga2 and the domain’s linker region are critical for driving self-renewal of hematopoietic stem cell2022

    • Author(s)
      Yuqi Sun; Sho Kubota; Mihoko Iimori; Ai Hamashima; Haruka Murakami; Jie Bai; Mariko Morii; Takako Yokomizo-Nakano; Motomi Osato; Kimi Araki; Goro Sashida
    • Journal Title

      International Journal of Hematology

      Volume: 115 Pages: 553-562

    • Related Report
      2021 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
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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