1. Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
2. Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
3. BioFrontier Laboratories, Kyowa Hakko Kogyo Co. Ltd, Machida-shi, Tokyo 194-8533, Japan
4. Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Honjo, Kumamoto 860-0811 Japan
5. Advanced Medical Discovery Institute, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada
6. These authors contributed equally to this work

Correspondence to: Atsushi Hirao^1,6Toshio Suda¹ Correspondence and requests for materials should be addressed to A.H. (Email: ahirao@sc.itc.keio.ac.jp) or T.S. (Email: sudato@sc.itc.keio.ac.jp).

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 stress^{1, 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 lymphoma^{3, 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 p16^INK4a-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.

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