Delia Domenico, Mizutani Shuki
Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy.
Kawasaki North Center for Childhood Developmental Disorder/Tokyo Medical and Dental University, 5-26-1 Katahira, Aso-ku, Kawasaki, 215-0003, Japan.
Int J Hematol. 2017 Sep;106(3):328-334. doi: 10.1007/s12185-017-2300-7. Epub 2017 Jul 13.
In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations. Besides favoring tumor formation and progression, molecular defects that directly or indirectly inactivate certain DDR pathways can provide a therapeutic opportunity, since a reduced ability to repair DNA lesions renders hemopoietic malignancies vulnerable to genotoxic drugs acting also through synthetic lethal interactions. Here, we discuss the essential role of DDR in HSC maintenance and protection against leukemogenesis, and how acquired DDR dysfunctions or pharmacological agents that block this pathway can be effectively exploited for the treatment of various hematopoietic malignancies.
在哺乳动物细胞中，DNA损伤反应（DDR）可防止DNA错误复制并传递给下一代，从而维持基因组稳定性。DDR的核心是相关的信号激酶ATM、ATR和DNA-PK，它们调节DNA修复及相关事件，如细胞周期检查点、染色质重塑、转录，最终导致细胞凋亡。多项研究结果突显了造血干细胞（HSC）中DDR的存在，这些细胞中DNA损伤的持续存在会促使其功能衰退并积累致白血病突变。除了促进肿瘤形成和进展外，直接或间接使某些DDR途径失活的分子缺陷可提供治疗机会，因为修复DNA损伤能力的降低使造血恶性肿瘤易受通过合成致死相互作用起作用的基因毒性药物影响。在此，我们讨论DDR在HSC维持及预防白血病发生中的重要作用，以及如何有效利用获得性DDR功能障碍或阻断该途径的药物来治疗各种造血系统恶性肿瘤。
