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Elucidating the mechanisms of clonal evolution of myeloid neoplasms with germline predisposition

Research Project

Project/Area Number 21K08394
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 InstitutionKyoto University

Principal Investigator

Kon Ayana  京都大学, 医学研究科, 特定講師 (20772403)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords骨髄異形成症候群 / 急性骨髄性白血病 / 胚細胞変異 / クローン進化 / DDX41遺伝子
Outline of Research at the Start

近年、新規の胚細胞・体細胞DDX41変異を有する骨髄系腫瘍が報告され、その多くの症例では、先天的にDDX41胚細胞変異を有し、対側アレルに体細胞変異を獲得することで骨髄系腫瘍を発症することが明らかとなった。これまでに申請者らは、DDX41変異に関するマウスモデルの解析を通じて、変異造血細胞では自然免疫伝達経路が細胞自律的に活性化し、造血不全を来すことを明らかにしたが、Ddx41胚細胞・体細胞変異を併せ持つ造血細胞がクローン選択を受ける分子病態については多くが不明である。本研究ではその分子病態を明らかすることを目指し、さらにはDDX41変異を標的とした新規治療法開発の可能性を検討する。

Outline of Final Research Achievements

In this study, we investigated the molecular mechanisms underlying the clonal selection of hematopoietic cells harboring DDX41 germline/somatic mutations, which were previously identified through genetic analysis of late-onset familial and sporadic myeloid neoplasms. We generated Ddx41 mutant mouse models and examined the molecular pathogenesis using methodology including single-cell and omics analysis. Through this, we have elucidated the cell-autonomous/non-autonomous molecular pathogenesis induced by the Ddx41 mutations. Furthermore, we investigated the potential for identifying new therapeutic targets based on our discoveries.

Academic Significance and Societal Importance of the Research Achievements

本研究では、先天性骨髄系腫瘍の最大のリスク因子であるDDX41胚細胞/体細胞変異に関して、変異をもつ細胞がクローン選択を受ける分子メカニズムの詳細な検討により、変異により惹起される細胞自律的/非自律的な分子病態を多角的に解明した点で、高い学術的な独自性を有する。さらに、新規治療標的の開発の可能性も検討し、がんの治療予後の向上に資する社会的意義の高い研究成果が得られた。本研究で新たに生じた疑問に関する検討を継続し、病態のさらなる理解とその制御による新たな治療法の開発を目指したい。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (16 results)

All 2024 2023 2022 2021

All Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (13 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] SETBP1 is dispensable for normal and malignant hematopoiesis2023

    • Author(s)
      Tanaka A, Nishimura K, Saika W, Kon A, Koike Y, Tatsumi H, Takeda J, Nomura M, Zang W, Nakayama M, Matsuda M, Yamazaki H, Fukumoto M, Ito H, Hayashi Y, Kitamura T, Kawamoto H, Takaori-Kondo A, Koseki H, Ogawa S
    • Journal Title

      Leukemia

      Volume: 37 Issue: 9 Pages: 1802-1811

    • DOI

      10.1038/s41375-023-01970-5

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Germ line <i>DDX41</i> mutations define a unique subtype of myeloid neoplasms2023

    • Author(s)
      Makishima H, Saiki R, Nannya Y, (17人省略), Kon A, (28人省略), Maciejewski JP, Ogawa S.
    • Journal Title

      Blood

      Volume: 141 Issue: 5 Pages: 534-549

    • DOI

      10.1182/blood.2022018221

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Amplified <i>EPOR</i>/<i>JAK2</i> Genes Define a Unique Subtype of Acute Erythroid Leukemia2022

    • Author(s)
      Takeda J, Kenichi Y, (9人省略), Kon A (12/41番目), (途中省略), Makishima H, Ogawa S
    • Journal Title

      Blood Cancer Discovery

      Volume: 3 Issue: 5 Pages: 410-427

    • DOI

      10.1158/2643-3230.bcd-21-0192

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Pathogenic Mechanisms of DDX41 Mutations in the Development of Myeloid Malignancies2024

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Azumi Tomita, Keisuke Kataoka, Nobuyuki Kakiuchi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      3rd Regional Symposium on Myelodysplastic Syndromes (MDSR 2024)
    • Related Report
      2023 Annual Research Report
  • [Presentation] Functional roles of DDX41 mutations in the development of myeloid malignancies2023

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Nobuyuki Kakiuchi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      the 17th International Congress on Myelodysplastic Syndromes
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional roles of germline and somatic DDX41 mutations in the pathogenesis of myeloid malignancies2023

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Nobuyuki Kakiuchi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      The 2nd JCA-AACR Precision Cancer Medicine International Conference
    • Related Report
      2023 Annual Research Report
  • [Presentation] Pathogenic Mechanisms of DDX41 Mutations in the Development of Myeloid Malignancies2023

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Nobuyuki Kakiuchi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      The 13th JSH International Symposium 2023 in Tsukuba
    • Related Report
      2023 Annual Research Report
  • [Presentation] Pathogenic Mechanisms of DDX41 Mutations in the Development of Myeloid Malignancies2023

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Nobuyuki Kakiuchi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Pathogenic Mechanisms of DDX41 Mutations in the Development of Myeloid Malignancies2023

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Nobuyuki Kakiuchi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      第85回日本血液学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Pathogenic Mechanisms of DDX41 Mutations in the Development of Myeloid Malignancies2023

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Nobuyuki Kakiuchi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      65th ASH Annual Meeting & Exposition
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elucidating the mechanism of clonal evolution of DDX41 mutated cells in myeloid malignancies2022

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      第81回日本癌学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] Elucidating the mechanism of clonal evolution of DDX41 mutated cells in myeloid malignancies2022

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka,Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      第84回日本血液学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] Functional roles of DDX41 mutations in the development of myeloid malignancies2022

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Nobuyuki Kakiuchi, Yotaro Ochi, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      27th Congress of EHA
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] The molecular pathogenesis of DDX41-mutated myeloid neoplasms2021

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Ryosaku Inagaki, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] The molecular pathogenesis of DDX41-mutated myeloid neoplasms2021

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Ryosaku Inagaki, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] Functional roles of DDX41 mutations in the development of myeloid malignancies2021

    • Author(s)
      Ayana Kon, Masahiro M Nakagawa, Keisuke Kataoka, Ryosaku Inagaki, Hideki Makishima, Manabu Nakayama, Haruhiko Koseki, Yasuhito Nannya, Seishi Ogawa
    • Organizer
      63rd ASH Annual Meeting and Exposition
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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