Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells.
Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells.
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DOI：
10.1016/j.stem.2012.05.013
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发表时间：
2012-07-06
期刊：
影响因子：
23.9
通讯作者：
Soulier, Jean
中科院分区：
文献类型：
--
作者：
Ceccaldi, Raphael;Parmar, Kalindi;Mouly, Enguerran;Delord, Marc;Kim, Jung Min;Regairaz, Marie;Pla, Marika;Vasquez, Nadia;Zhang, Qing-Shuo;Pondarre, Corinne;de Latour, Regis Peffault;Gluckman, Eliane;Cavazzana-Calvo, Marina;Leblanc, Thierry;Larghero, Jerome;Grompe, Markus;Socie, Gerard;D'Andrea, Alan D.;Soulier, Jean
Fanconi贫血(FA)是一种遗传性DNA修复缺陷综合征。FA患者在儿童时期经历了进行性骨髓衰竭(BMF)，这通常需要异基因造血干细胞移植。到目前为止，这种BMF的发病机制尚不清楚。我们发现FA患者的造血干细胞和祖细胞(HSPC)存在严重的缺陷，这种缺陷在临床BMF发病之前就存在。作为对复制应激和未解决的DNA损伤的反应，P53在FA细胞中被过度激活，并触发晚期依赖p21CDKN 1a的G0/G1细胞周期停滞。P53的敲除挽救了在几个体外和体内模型中观察到的HSPC缺陷，包括人FA或FA样细胞。综上所述，我们的结果确认细胞应激和DNA损伤累积的加剧的p53/p21“生理”反应是FA患者进行性HSPC消除的中心机制，并对临床护理具有一定的指导意义。
Fanconi anemia (FA) is an inherited DNA repair deficiency syndrome. FA patients undergo progressive bone marrow failure (BMF) during childhood, which frequently requires allogeneic hematopoietic stem cell transplantation. The pathogenesis of this BMF has been elusive to date. Here we found that FA patients exhibit a profound defect in hematopoietic stem and progenitor cells (HSPCs) that is present before the onset of clinical BMF. In response to replicative stress and unresolved DNA damage, p53 is hyperactivated in FA cells and triggers a late p21Cdkn1a-dependent G0/G1 cell-cycle arrest. Knockdown of p53 rescued the HSPC defects observed in several in vitro and in vivo models, including human FA or FA-like cells. Taken together, our results identify an exacerbated p53/p21 “physiological” response to cellular stress and DNA damage accumulation as a central mechanism for progressive HSPC elimination in FA patients, and have implications for clinical care.
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影响因子：
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作者：
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