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Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells

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  • Keisuke Ito

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine
    Keio University School of Medicine)

  • Atsushi Hirao

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

  • Fumio Arai

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

  • Sahoko Matsuoka

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

  • Keiyo Takubo

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

  • Isao Hamaguchi

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

  • Kana Nomiyama

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

  • Kentaro Hosokawa

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

  • Kazuhiro Sakurada

    (Kyowa Hakko Kogyo Co. Ltd)

  • Naomi Nakagata

    (Center for Animal Resources and Development, Kumamoto University)

  • Yasuo Ikeda

    (Keio University School of Medicine)

  • Tak W. Mak

    (University of Toronto)

  • Toshio Suda

    (The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine)

Abstract

The ‘ataxia telangiectasia mutated’ (Atm) gene maintains genomic stability by activating a key cell-cycle checkpoint in response to DNA damage, telomeric instability or oxidative stress1,2. Mutational inactivation of the gene causes an autosomal recessive disorder, ataxia–telangiectasia, characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature ageing and a high incidence of lymphoma3,4. Here we show that ATM has an essential function in the reconstitutive capacity of haematopoietic stem cells (HSCs) but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-/- mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of Atm-/- HSCs, resulting in the prevention of bone marrow failure. Activation of the p16INK4a-retinoblastoma (Rb) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-/- HSCs. These results show that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress.

Suggested Citation

  • Keisuke Ito & Atsushi Hirao & Fumio Arai & Sahoko Matsuoka & Keiyo Takubo & Isao Hamaguchi & Kana Nomiyama & Kentaro Hosokawa & Kazuhiro Sakurada & Naomi Nakagata & Yasuo Ikeda & Tak W. Mak & Toshio S, 2004. "Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells," Nature, Nature, vol. 431(7011), pages 997-1002, October.
  • Handle: RePEc:nat:nature:v:431:y:2004:i:7011:d:10.1038_nature02989
    DOI: 10.1038/nature02989
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    Cited by:

    1. Weam S. Shahin & Shima O. Ebed & Scott R. Tyler & Branko Miljkovic & Soon H. Choi & Yulong Zhang & Weihong Zhou & Idil A. Evans & Charles Yeaman & John F. Engelhardt, 2023. "Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Hans B Sieburg & Giulio Cattarossi & Christa E Muller-Sieburg, 2013. "Lifespan Differences in Hematopoietic Stem Cells are Due to Imperfect Repair and Unstable Mean-Reversion," PLOS Computational Biology, Public Library of Science, vol. 9(4), pages 1-15, April.
    3. Anthony Veltri & Christopher M. R. Lang & Gaia Cangiotti & Chim Kei Chan & Wen-Hui Lien, 2022. "ROR2 regulates self-renewal and maintenance of hair follicle stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Mary T. Scott & Wei Liu & Rebecca Mitchell & Cassie J. Clarke & Ross Kinstrie & Felix Warren & Hassan Almasoudi & Thomas Stevens & Karen Dunn & John Pritchard & Mark E. Drotar & Alison M. Michie & Hea, 2024. "Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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