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

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 and Toshio Suda ()
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Keisuke Ito: The Sakaguchi Laboratory of Developmental Biology, 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

Nature, 2004, vol. 431, issue 7011, 997-1002

Abstract: 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.

Date: 2004
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DOI: 10.1038/nature02989

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