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Pathophysiological role of extracellular vesicles in donor cell-derived leukemia

Research Project

Project/Area Number 20K08749
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 InstitutionKanazawa University

Principal Investigator

Baba Tomohisa  金沢大学, がん進展制御研究所, 准教授 (00452095)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
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)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords細胞外小胞 / 細胞質内DNAセンサー / 造血幹細胞移植療法 / 骨髄性白血病 / 慢性骨髄性白血病 / ドナー細胞由来白血病 / 白血病 / 骨髄移植治療
Outline of Research at the Start

多様な病態を示す白血病に対して、共通して適用できる造血幹細胞移植療法は、血液臨床上強力な治療手段であると考えられている。しかし、治療後に残存した白血病細胞からの白血病の再発に加えて、移植した正常ドナー骨髄細胞が新たに白血病化する、いわゆるドナー細胞由来白血病による再発の報告が近年増加しており、臨床上重大な問題となっている。
本研究では、原因不明の疾患であるドナー細胞由来白血病の発症機序を明らかにするために、実験モデルを独自に開発し、それを用いた詳細な解析を行う。さらには、その発症予防法を開発することで、より安全で効果的な骨髄移植治療法の確立を目指す。

Outline of Final Research Achievements

In this study, we established an experimental mouse model of donor cell-derived leukemia (DCL), a rare disease that is known to occur after hematopoietic stem cell transplantation (HSCT). Pathophysiological analysis revealed that extracellular vesicles derived from leukemia cells, which contain high levels of double-stranded DNA fragments, are horizontally transferred to donor HSCs. This transfer leads to the malignant transformation of donor HSCs through the activation of the cytosolic DNA sensor signaling pathway.

Academic Significance and Societal Importance of the Research Achievements

造血幹細胞移植治療後に、正常であるはずのドナー骨髄細胞から、骨髄異形成症候群(MDS)やAML、ALLなどの種々の白血病が発症するDCLは、原因不明で不可思議な疾患である。また、DCLは、通常の再発白血病と比べて悪性度が高いことから、世界的に臨床上大きな問題となっている。本研究成果から、白血病細胞由来の細胞外小胞が原因の一つとなっている可能性が強く示唆されており、DCLの病態解明にかかわる重要な知見であると考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (9 results)

All 2022 2021 2020 Other

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (3 results) Remarks (1 results)

  • [Journal Article] CCR2- and CCR5-mediated macrophage infiltration contributes to glomerular endocapillary hypercellularity in antibody-induced lupus nephritis2021

    • Author(s)
      Zoshima T, Baba T, Tanabe Y, Ishida Y, Nakatani K, Nagata M, Mukaida N, Kawano M.
    • Journal Title

      Rheumatology (Oxford)

      Volume: - Issue: 7 Pages: 3033-3048

    • DOI

      10.1093/rheumatology/keab825

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway2021

    • Author(s)
      Baba Tomohisa、Yoshida Takeshi、Tanabe Yamato、Nishimura Tatsunori、Morishita Soji、Gotoh Noriko、Hirao Atsushi、Hanayama Rikinari、Mukaida Naofumi
    • Journal Title

      Cell Death & Disease

      Volume: 12 Issue: 4 Pages: 322-322

    • DOI

      10.1038/s41419-021-03587-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expansion of senescent megakaryocyte-lineage cells maintains CML cell leukemogenesis2020

    • Author(s)
      Tanabe Yamato、Kawamoto Shimpei、Takaku Tomoiku、Morishita Soji、Hirao Atsushi、Komatsu Norio、Hara Eiji、Mukaida Naofumi、Baba Tomohisa
    • Journal Title

      Blood Advances

      Volume: 4 Issue: 24 Pages: 6175-6188

    • DOI

      10.1182/bloodadvances.2020003117

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone2020

    • Author(s)
      Di Zhang, Sadahiro Iwabuchi, Tomohisa Baba, Shin-Ichi Hashimoto, Naofumi Mukaida, So-Ichiro Sasaki
    • Journal Title

      Cancers (Basel)

      Volume: 12 Issue: 10 Pages: 3003-3003

    • DOI

      10.3390/cancers12103003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two-Faced Roles of Tumor-Associated Neutrophils in Cancer Development and Progression2020

    • Author(s)
      Mukaida Naofumi、Sasaki So-ichiro、Baba Tomohisa
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 10 Pages: 3457-3457

    • DOI

      10.3390/ijms21103457

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Cytosolic DNA-sensor signaling potentiates AML differentiation therapy to induce an irreversible cell differentiation.2022

    • Author(s)
      馬場智久、城村由和
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Autophagy inhibitor selectively induces cytotoxicity against myeloid leukemia cells by accumulating cytosolic DNA.2021

    • Author(s)
      馬場智久
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 慢性骨髄性白血病のTKI治療に対するオートファジー阻害剤の併用効果2020

    • Author(s)
      馬場智久、向田直史
    • Organizer
      第24回日本がん分子標的治療学会学術集会
    • Related Report
      2020 Research-status Report
  • [Remarks] 金沢大学がん進展制御研究所、がん・老化生物学研究分野ホームページ

    • URL

      https://www.csb-kucri.com

    • Related Report
      2022 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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