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Age dependent MLL-fusion leukemia development

Research Project

Project/Area Number 21K08421
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 InstitutionOkayama University (2023)
Kumamoto University (2021-2022)

Principal Investigator

Kubota Sho  岡山大学, 医歯薬学域, 助教 (70747831)

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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords白血病 / エピゲノム / MLL / 小児 / 年齢依存 / 造血幹細胞 / がん / 造血
Outline of Research at the Start

MLL融合がん遺伝子を原因とした白血病は、成人に比べ胎児・新生児の生後一年未満の患者で非常に高い頻度で見られることの明確な理由は数十年いまだ不明なままである。小児と成人で発症頻度に10倍以上の違いがあり、非常に大きな臨床的な違いがあるため、申請者は重要な意味があると考えた。そこで、トランスクリプトーム・エピゲノムを組み合わせた解析を用いて、白血病発症依存性を決定する因子の探索を行う。

Outline of Final Research Achievements

We examined the effects of age-dependent differences in HSC properties on the development of leukemia and analyzed a developmental time-dependent model of leukemogenesis. It is also known that continuous transplantation of bone marrow from mice can add inflammatory stress to HSCs, which also occurs in aging mice, and change the properties of HSCs. We examined the effects of these changes in the intracellular environment of HSCs on the development of leukemia and analyzed HSC stress-dependent leukemogenesis. Then, based on the validation results obtained from the two models, we analyzed the HSC properties that regulate leukemogenesis.

Academic Significance and Societal Importance of the Research Achievements

MLL融合がん遺伝子による白血病は年齢との関係性が非常に高いことがよく知られている。成人期における白血病の5%程度でMLL融合がん遺伝子が検出されるが、新生児期においては白血病の50-80%の頻度でMLL融合がん遺伝子が検出される。t(9;11)によって生じるMLL融合がん遺伝子の一つであるMLL-AF9は、AMLを引き起こす主要なMLL融合がん遺伝子である。MLL融合がん遺伝子を原因とした白血病は、成人に比べ胎児・新生児の生後一年未満の患者で非常に高い頻度で見られることの明確な理由は数十年いまだ不明なままである。本研究成果は、MLL融合由来白血病発症機構を理解することで治療の基礎基盤となる。

Report

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

    (13 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (1 results) Journal Article (8 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (4 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

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

    • Related Report
      2021 Research-status Report
  • [Journal Article] Methyl vinyl ketone and its analogs covalently modify PI3K and alter physiological functions by inhibiting PI3K signaling2024

    • Author(s)
      Morimoto Atsushi、Takasugi Nobumasa、Pan Yuexuan、Kubota Sho、Dohmae Naoshi、Abiko Yumi、Uchida Koji、Kumagai Yoshito、Uehara Takashi
    • Journal Title

      Journal of Biological Chemistry

      Volume: 300 Issue: 3 Pages: 105679-105679

    • DOI

      10.1016/j.jbc.2024.105679

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Attenuation of protein arginine dimethylation via S-nitrosylation of protein arginine methyltransferase 12024

    • Author(s)
      Rikako Taniguchi, Yuto Moriya, Naoshi Dohmae, Takehiro Suzuki, Kengo Nakahara, Sho Kubota, Nobumasa Takasugi, Takashi Uehara.
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 154 Issue: 3 Pages: 209-217

    • DOI

      10.1016/j.jphs.2023.12.012

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiple myeloma?associated DIS3 gene is essential for hematopoiesis, but loss of DIS3 is insufficient for myelomagenesis2024

    • Author(s)
      Ohguchi Hiroto、Ohguchi Yasuyo、Kubota Sho、Etoh Kan、Hamashima Ai、Usuki Shingo、Yokomizo-Nakano Takako、Bai Jie、Masuda Takeshi、Kawano Yawara、Harada Takeshi、Nakao Mitsuyoshi、Minami Takashi、Hideshima Teru、Araki Kimi、Sashida Goro
    • Journal Title

      Blood Neoplasia

      Volume: 1 Issue: 1 Pages: 100005-100005

    • DOI

      10.1016/j.bneo.2024.100005

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CARD11 mutation and HBZ expression induce lymphoproliferative disease and adult T-cell leukemia/lymphoma2022

    • Author(s)
      Takuro Kameda, ...Sho Kubota.... , Kazuya Shimoda
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 1309-1309

    • DOI

      10.1038/s42003-022-04284-x

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [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 Research-status Report 2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] HMGN3 represses transcription of epithelial regulators to promote migration of cholangiocarcinoma in a SNAI2-dependent manner2022

    • Author(s)
      Supannika Sorin, Sho Kubota, Sofiane Hamidi, Takako Yokomizo-Nakano, Kulthida Vaeteewoottacharn, Sopit Wongkham, Sakda Waraasawapati, Chawalit Pairojkul, Jie Bai, Mariko Morii, Guojun Sheng, Kanlayanee Sawanyawisuth, Goro Sashida
    • Journal Title

      The FASEB Journal

      Volume: 36 Issue: 7

    • DOI

      10.1096/fj.202200386r

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration2022

    • Author(s)
      Umemoto Terumasa、Johansson Alban、Ahmad Shah Adil Ishtiyaq、Hashimoto Michihiro、Kubota Sho、Kikuchi Kenta、Odaka Haruki、Era Takumi、Kurotaki Daisuke、Sashida Goro、Suda Toshio
    • Journal Title

      The EMBO Journal

      Volume: 41 Issue: 8 Pages: 1-20

    • DOI

      10.15252/embj.2021109463

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Hmga2による炎症応答制御を介した造血幹細胞再生機構と骨髄異形成症候群2023

    • Author(s)
      久保田 翔
    • Organizer
      第97回日本薬理学会年会 シンポジウム講演
    • Related Report
      2023 Annual Research Report
  • [Presentation] HMGA による造血幹細胞制御機構の解析2023

    • Author(s)
      久保田翔、白潔、森井真理子 、平山真弓 、指田吾郎
    • Organizer
      第 27 回造血器腫瘍研究会
    • Related Report
      2022 Research-status Report
  • [Presentation] Inflammatory stress tolerance of hematopoietic stem cell is activated by Hmga22022

    • Author(s)
      Sho Kubota
    • Organizer
      The 5th KU-KAIST Joint Symposium
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] HMGA2 maintains hematopoietic stem cell via pleiotropic regulation of the transcription in stress conditions2021

    • Author(s)
      Sho Kubota, Yuqi Sun, Jie Bai, Takako Yokomizo-Nakano, Mariko Morii, Takako Ideue, Motomi Osato, Terumasa Umemoto, Kimi Araki, and Goro Sashida
    • Organizer
      Annual meeting of American Society of Hematology
    • 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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