Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells
Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells
复制标题
DOI：
10.1038/nature07618
复制
发表时间：
2009-01-01
期刊：
影响因子：
64.8
通讯作者：
Pelicci, Pier Giuseppe
中科院分区：
文献类型：
--
作者：
Viale, Andrea;De Franco, Francesca;Pelicci, Pier Giuseppe
具有干细胞特性的罕见细胞是白血病发展和延续的组成部分。干细胞的一个定义性特征是它们的自我更新能力，这在白血病干细胞中显著延长。然而，潜在的分子机制在很大程度上是未知的。在这里，我们证明了细胞周期抑制剂p21的表达对于维持白血病干细胞的自我更新是必不可少的。白血病相关癌基因在小鼠造血干细胞（HSC）中的表达诱导DNA损伤并激活p21依赖性细胞反应，这导致可逆的细胞周期停滞和DNA修复。活化的p21在防止白血病干细胞的过度DNA损伤积累和功能衰竭中是至关重要的。这些数据揭示了p21的致癌潜力，并表明抑制DNA修复机制可能作为根除缓慢增殖的白血病干细胞的有效策略。
Rare cells with the properties of stem cells are integral to the development and perpetuation of leukaemias. A defining characteristic of stem cells is their capacity to self- renew, which is markedly extended in leukaemia stem cells. The underlying molecular mechanisms, however, are largely unknown. Here we demonstrate that expression of the cell- cycle inhibitor p21 is indispensable for maintaining self- renewal of leukaemia stem cells. Expression of leukaemia- associated oncogenes in mouse haematopoietic stem cells ( HSCs) induces DNA damage and activates a p21- dependent cellular response, which leads to reversible cell- cycle arrest and DNA repair. Activated p21 is critical in preventing excess DNA- damage accumulation and functional exhaustion of leukaemic stem cells. These data unravel the oncogenic potential of p21 and suggest that inhibition of DNA repair mechanisms might function as potent strategy for the eradication of the slowly proliferating leukaemia stem cells.