Biechonski Shahar, Yassin Muhammad, Milyavsky Michael
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Carcinogenesis. 2017 Apr 1;38(4):367-377. doi: 10.1093/carcin/bgx002.
Self-renewing and multipotent hematopoietic stem cells (HSCs) maintain lifelong hematopoiesis. Their enormous regenerative potential coupled with lifetime persistence in the body, in contrast with the Progenitors, demand tight control of HSCs genome stability. Indeed, failure to accurately repair DNA damage in HSCs is associated with bone marrow failure and accelerated leukemogenesis. Recent observations exposed remarkable differences in several DNA-damage response (DDR) aspects between HSCs and Progenitors, especially in their DNA-repair capacities and susceptibility to apoptosis. Human HSCs in comparison with Progenitors exhibit delayed DNA double-strand break rejoining, persistent DDR signaling activation, higher sensitivity to the cytotoxic effects of ionizing radiation and attenuated expression of DNA-repair genes. Importantly, the distinct DDR of HSCs was also documented in mouse models. Nevertheless, physiological significance and the molecular basis of the HSCs-specific DDR features are only partially understood. Taking radiation-induced DDR as a paradigm, this review will focus on the current advances in understanding the role of cell-intrinsic DDR regulators and the cellular microenvironment in balancing stemness with genome stability. Pre-leukemia HSCs and clonal hematopoiesis evolvement will be discussed as an evolutionary compromise between the need for lifelong blood regeneration and DDR. Uniquely for this review, we outline the differences in HSCs-related DDR as highlighted by various experimental systems and attempt to provide their critical analysis.
自我更新和多能造血干细胞（HSCs）维持终身造血功能。与祖细胞相比，它们巨大的再生潜力以及在体内的终身持续性要求对HSCs基因组稳定性进行严格控制。事实上，HSCs中DNA损伤未能准确修复与骨髓衰竭和白血病发生加速有关。最近的观察结果揭示了HSCs和祖细胞在几个DNA损伤反应（DDR）方面存在显著差异,特别是在它们的DNA修复能力和对凋亡的敏感性方面。与祖细胞相比，人类HSCs表现出DNA双链断裂重新连接延迟、DDR信号持续激活、对电离辐射的细胞毒性作用更敏感以及DNA修复基因表达减弱。重要的是，在小鼠模型中也记录到了HSCs独特的DDR。然而，HSCs特异性DDR特征的生理意义和分子基础仅得到部分理解。以辐射诱导的DDR为范例，本综述将聚焦于当前在理解细胞内在DDR调节因子和细胞微环境在平衡干性与基因组稳定性方面作用的进展。白血病前期HSCs和克隆性造血演变将作为终身血液再生需求与DDR之间的一种进化折衷进行讨论。本综述的独特之处在于，我们概述了各种实验系统所突出的与HSCs相关的DDR差异，并试图对其进行批判性分析。
