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, Toshio Suda

Research output: Contribution to journalArticle

807 Citations (Scopus)

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. 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. 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.

Original languageEnglish
Pages (from-to)997-1002
Number of pages6
JournalNature
Volume431
Issue number7011
DOIs
Publication statusPublished - 2004 Oct 21

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Ataxia Telangiectasia
Hematopoietic Stem Cells
Oxidative Stress
Reactive Oxygen Species
Bone Marrow
Retinoblastoma Genes
p16 Genes
Premature Aging
Cerebellar Ataxia
Genomic Instability
Telomere
Gene Silencing
Spermatogenesis
Cell Cycle Checkpoints
DNA Damage
Lymphoma
Incidence
Genes

ASJC Scopus subject areas

  • General

Cite this

Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., ... Suda, T. (2004). Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature, 431(7011), 997-1002. https://doi.org/10.1038/nature02989

Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. / Ito, Keisuke; Hirao, Atsushi; Arai, Fumio; Matsuoka, Sahoko; Takubo, Keiyo; Hamaguchi, Isao; Nomiyama, Kana; Hosokawa, Kentaro; Sakurada, Kazuhiro; Nakagata, Naomi; Ikeda, Yasuo; Mak, Tak W.; Suda, Toshio.

In: Nature, Vol. 431, No. 7011, 21.10.2004, p. 997-1002.

Research output: Contribution to journalArticle

Ito, K, Hirao, A, Arai, F, Matsuoka, S, Takubo, K, Hamaguchi, I, Nomiyama, K, Hosokawa, K, Sakurada, K, Nakagata, N, Ikeda, Y, Mak, TW & Suda, T 2004, 'Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells', Nature, vol. 431, no. 7011, pp. 997-1002. https://doi.org/10.1038/nature02989
Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004 Oct 21;431(7011):997-1002. https://doi.org/10.1038/nature02989
Ito, Keisuke ; Hirao, Atsushi ; Arai, Fumio ; Matsuoka, Sahoko ; Takubo, Keiyo ; Hamaguchi, Isao ; Nomiyama, Kana ; Hosokawa, Kentaro ; Sakurada, Kazuhiro ; Nakagata, Naomi ; Ikeda, Yasuo ; Mak, Tak W. ; Suda, Toshio. / Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. In: Nature. 2004 ; Vol. 431, No. 7011. pp. 997-1002.
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