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

Nature volume 431, pages 997–1002 (2004)Cite this article

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.

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Figure 1: Defective haematopoiesis in the absence of ATM.
Figure 2: The defect in Atm-/- HSC function is caused by elevated ROS.
Figure 3: Elevated ROS induces upregulation of p16INK4a and p19ARF in Atm-/- KSL cells.
Figure 4: Activation of the p16INK4a-Rb pathway causes the defect in stem cell function in Atm-/- mice.

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Acknowledgements

We thank H. Saya for helpful discussions, T. Kiyono for providing E6 and E7 cDNA, A. Iwama for providing mouse Bmi-1 cDNA and virus, F. Ishikawa for providing mouse TERT cDNA, T. Kitamura for providing retroviral vector pMY, A. Ono for technical support, and M. Saunders for scientific editing. A.H. was supported by grants-in-aid from the Cancer Research and from the Stem Cell Research of the Ministry of Education, Science, Sports, and Culture, Japan. T.S. was supported by a grant-in-aid from the Research for the Future Program and the Specially Promoted Research of the Ministry of Education, Science, Sports, and Culture, Japan.

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Author notes

  1. Keisuke Ito and Atsushi Hirao: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, 35 Shinano-machi, 160-8582, Shinjuku-ku, Tokyo, Japan

    Keisuke Ito, Atsushi Hirao, Fumio Arai, Sahoko Matsuoka, Keiyo Takubo, Isao Hamaguchi, Kana Nomiyama, Kentaro Hosokawa & Toshio Suda

  2. Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinano-machi, 160-8582, Shinjuku-ku, Tokyo, Japan

    Keisuke Ito & Yasuo Ikeda

  3. BioFrontier Laboratories, Kyowa Hakko Kogyo Co. Ltd, 194-8533, Machida-shi, Tokyo, Japan

    Kazuhiro Sakurada

  4. Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, 860-0811, Honjo, Kumamoto, Japan

    Naomi Nakagata

  5. Advanced Medical Discovery Institute, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Suite 706, Ontario, M5G 2C1, Toronto, Canada

    Tak W. Mak

Authors
  1. Keisuke Ito
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Correspondence to Atsushi Hirao or Toshio Suda.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Table 1

List of PCR primers used in the study (JPG 80 kb)

Supplementary Figure 1

Normal progenitors in eight-week-old ATM-/- mice. (JPG 217 kb)

Supplementary Figure 2

Normal homing capacity of ATM-/- HSCs. (JPG 141 kb)

Supplementary Figure 3

No increased apoptosis in ATM-/- cells. (JPG 96 kb)

Supplementary Figure 4

Defective haematopoiesis in 24-week-old ATM-/- mice. (JPG 161 kb)

Supplementary Figure 5

Normal telomere length in ATM-/- BM cells. (JPG 73 kb)

Supplementary Figure 6

Prevention of BM failure in aged ATM-/- mice by long-term NAC treatment. (JPG 181 kb)

Supplementary Figure 7

Upregulation of p16INK4a and p19ARF in ATM-/- KSL cells. (JPG 122 kb)

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Ito, K., Hirao, A., Arai, F. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004). https://doi.org/10.1038/nature02989

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