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Functional elucidation of shelterin factor TIN2 in leukemic stem cells and its application to the development of novel therapeutic strategies

Research Project

Project/Area Number 19K22638
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 InstitutionKyushu University

Principal Investigator

Arai Fumio  九州大学, 医学研究院, 教授 (90365403)

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: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Keywords造血幹細胞 / 白血病幹細胞 / TIN2 / ミトコンドリア / 活性酸素種 / シェルタリン / POT1 / シェルタリン因子 / 代謝制御
Outline of Research at the Start

白血病幹細胞は正常造血幹細胞とは異なり、ミトコンドリアに局在するTIN2がエネルギー代謝を制御し、増殖・維持に寄与している可能性が考えられる。本研究では、白血病幹細胞におけるミトコンドリアTIN2の機能実態を明らかにするとともに、ROSに対する抵抗性・生存優位性を規定する機構を解明する。特に、ミトコンドリアTIN2によって誘導される代謝制御因子および抗アポトーシス因子を同定する。さらに、TIN2の細胞内局在の制御による白血病幹細胞の特異的除去について検討を進める。また、正常造血幹細胞との「違い」を基に、がん治療のための新規標的を同定し、がん幹細胞の選択的除去に向けた技術基盤の確立を目指す。

Outline of Final Research Achievements

Shelterin complex (consisting of POT1, TPP1, TIN2, TRF1, TRF2, and RAP1) play essential roles in maintaining HSC function. We found that TIN2 localized in the mitochondria of HSCs increased reactive oxygen species (ROS) production and decreased self-renewal capacity. POT1 and TPP1 contributed to inhibiting the mitochondrial transfer of TIN2. On the other hand, TIN2 expression was upregulated in leukemic GMP (L-GMP), which possibly contributes to the energy metabolism in mitochondria in L-GMP. However, overexpression of TIN2 in L-GMP inhibited proliferation. Therefore, we need further investigation to clarify the function of mitochondrial TIN2 in leukemic stem cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、シェルタリン因子TIN2がミトコンドリアに移行した場合、正常造血幹細胞では自己複製を抑制するが、白血病幹細胞では増殖に働くということを見出している。ミトコンドリアTIN2が正常幹細胞とがん幹細胞で異なる作用をもつという点は、新規性の高い成果であると考えられる。
今後、TPP1とPOT1aのタンパク導入によるミトコンドリアTIN2の機能抑制は、正常造血幹細胞の体外増幅と白血病幹細胞の抑制の両方に応用が可能であり、再生医療とがん治療の発展に同時に貢献出来ると考えられる。

Report

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

    (12 results)

All 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (7 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 7 results,  Open Access: 3 results) Remarks (2 results)

  • [Int'l Joint Research] University of Southampton(英国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] RWTH Aachen, アーヘン工科大学(ドイツ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] サウサンプトン大学(英国)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Modeling Stem Cell Fates using Non-Markov Processes2021

    • Author(s)
      Stumpf Patrick S.、Arai Fumio、MacArthur Ben D.
    • Journal Title

      Cell Stem Cell

      Volume: 28 Issue: 2 Pages: 187-190

    • DOI

      10.1016/j.stem.2021.01.009

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Machine Learning of Hematopoietic Stem Cell Divisions from Paired Daughter Cell Expression Profiles Reveals Effects of Aging on Self-Renewal2020

    • Author(s)
      Arai Fumio、Stumpf Patrick S.、Ikushima Yoshiko M.、Hosokawa Kentaro、Roch Aline、Lutolf Matthias P.、Suda Toshio、MacArthur Ben D.
    • Journal Title

      Cell Systems

      Volume: 11 Issue: 6 Pages: 640-652

    • DOI

      10.1016/j.cels.2020.11.004

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45? TER119?Erythroid and Lymphoid Progenitors2020

    • Author(s)
      Gotoh Kazuhito、Kunisaki Yuya、Mizuguchi Soichi、Setoyama Daiki、Hosokawa Kentaro、Yao Hisayuki、Nakashima Yuya、Yagi Mikako、Uchiumi Takeshi、Semba Yuichiro、Nogami Jumpei、Akashi Koichi、Arai Fumio、Kang Dongchon
    • Journal Title

      iScience

      Volume: 23 Issue: 11 Pages: 101654-101654

    • DOI

      10.1016/j.isci.2020.101654

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel method to purify neutrophils enables functional analysis of zebrafish hematopoiesis2020

    • Author(s)
      Konno Katsuhiro、Kulkeaw Kasem、Sasada Manabu、Nii Takenobu、Kaneyuki Ayako、Ishitani Tohru、Arai Fumio、Sugiyama Daisuke
    • Journal Title

      Genes to Cells

      Volume: 25 Issue: 12 Pages: 770-781

    • DOI

      10.1111/gtc.12810

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heterogeneity and ‘memory’ in stem cell populations2020

    • Author(s)
      Stumpf Patrick S、Arai Fumio、MacArthur Ben D
    • Journal Title

      Physical Biology

      Volume: 17 Issue: 6 Pages: 065013-065013

    • DOI

      10.1088/1478-3975/abba85

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Transfer learning efficiently maps bone marrow cell types from mouse to human using single-cell RNA sequencing2020

    • Author(s)
      Stumpf Patrick S.、Du Xin、Imanishi Haruka、Kunisaki Yuya、Semba Yuichiro、Noble Timothy、Smith Rosanna C. G.、Rose-Zerili Matthew、West Jonathan J.、Oreffo Richard O. C.、Farrahi Katayoun、Niranjan Mahesan、Akashi Koichi、Arai Fumio、MacArthur Ben D.
    • Journal Title

      Communications Biology

      Volume: 3 Issue: 1 Pages: 736-746

    • DOI

      10.1038/s42003-020-01463-6

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo.2019

    • Author(s)
      Kobayashi H, Morikawa T, Okinaga A, Hamano F, Hashidate-Yoshida T, Watanuki S, Hishikawa D, Shindou H, Arai F, Kabe Y, Suematsu M, Shimizu T, Takubo K.
    • Journal Title

      Cell Reports

      Volume: 28 Issue: 1 Pages: 145-158

    • DOI

      10.1016/j.celrep.2019.06.008

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Remarks] 幹細胞再生修復医学分野ホームページ

    • URL

      https://www.lab.med.kyushu-u.ac.jp/scr/

    • Related Report
      2020 Annual Research Report
  • [Remarks] 九州大学大学院医学研究院幹細胞再生修復医学分野ホームページ

    • URL

      http://www.scr.med.kyushu-u.ac.jp

    • Related Report
      2019 Research-status Report

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

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