Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.
Int J Hematol. 2011 Apr;93(4):434-439. doi: 10.1007/s12185-011-0793-z. Epub 2011 Mar 9.
Hematopoietic stem cells (HSCs) maintain hematopoietic homeostasis throughout a mammal's lifespan through self-renewal and differentiation into mature blood cells. Within a bone marrow niche, HSCs adopt a quiescent state and remain in the non-dividing, G0 phase of the cell cycle. It was recently shown that maintenance of genomic integrity is crucial for the preservation of self-renewal capacity of HSCs. In this review, we focus on progress in elucidating the roles of reactive oxygen species (ROS) and DNA damage responses (DDR) in maintaining genomic integrity, and thus HSC function. Several studies have demonstrated that inappropriate ROS levels arising from disruption of the Atm, PI3K-Akt, or Mdm2-p53 pathways impair HSC function in vivo. Intriguing evidence that stem cells use specific DDR mechanisms is also accumulating. Although murine HSCs are more resistant than progenitor cells to mild DNA damage in vivo, the surviving HSCs frequently acquire genetic aberrations that can lead to leukemogenesis. Indeed, non-dividing HSCs employ the error-prone non-homologous end-joining pathway of DNA repair to fix DNA breaks, whereas progenitors undergo apoptosis; proliferating HSCs employ the high-fidelity homologous recombination mechanism. Dissection of HSC-specific mechanisms for the maintenance of genomic integrity may provide valuable insights into the biology of both HSCs and leukemia stem cells.
造血干细胞（HSCs）通过自我更新和分化为成熟血细胞来维持哺乳动物整个生命周期中的造血稳态。在骨髓龛内，HSCs 处于静止状态，停留在细胞周期的非分裂、G0 期。最近的研究表明，基因组完整性的维持对于维持 HSCs 的自我更新能力至关重要。在这篇综述中，我们重点讨论了阐明活性氧（ROS）和 DNA 损伤反应（DDR）在维持基因组完整性和 HSC 功能方面的作用的进展。几项研究表明，来自 Atm、PI3K-Akt 或 Mdm2-p53 途径破坏的不适当 ROS 水平会损害体内 HSC 的功能。令人着迷的是，干细胞使用特定的 DDR 机制的证据也在不断积累。虽然与祖细胞相比，小鼠 HSCs 对体内轻度 DNA 损伤更具抗性，但存活的 HSCs 经常获得可导致白血病发生的遗传异常。事实上，非分裂的 HSCs 利用易错的非同源末端连接途径修复 DNA 断裂，而祖细胞则通过凋亡来修复；增殖的 HSCs 利用高保真同源重组机制。剖析 HSC 维持基因组完整性的特异性机制可能为 HSCs 和白血病干细胞的生物学提供有价值的见解。
