Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
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DOI：
10.1038/nature02989
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发表时间：
2004-10-21
期刊：
影响因子：
64.8
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Ito, K;Hirao, A;Suda, T
‘共济失调毛细血管扩张突变’(ATM)基因通过激活一个关键的细胞周期检查点来维持基因组的稳定性，以应对DNA损伤、端粒不稳定或氧化应激(1，2)。该基因的突变失活会导致一种常染色体隐性疾病，即共济失调-毛细血管扩张，其特征是免疫缺陷、进行性小脑性共济失调、眼皮肤毛细血管扩张、精子生成缺陷、过早衰老和淋巴瘤的高发病率(3，4)。在这里，我们表明ATM在造血干细胞(HSCs)的重建能力中具有重要的功能，但对祖细胞的增殖或分化不是那么重要，是一种端粒不依赖的方式。年龄超过24周的ATM(-/-)小鼠表现出进行性骨髓衰竭，这是由于HSC功能缺陷导致的，而HSC功能缺陷与活性氧含量升高有关。抗氧化剂的治疗恢复了ATM(-/-)HSCs的重建能力，从而防止了骨髓衰竭。P16(INK4a)-视网膜母细胞瘤(Rb)基因产物通路的激活是导致ATM(-/-)HSCs失效的原因。这些结果表明，HSCs的自我更新能力依赖于ATM介导的氧化应激抑制。
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.