Esposito Maria Teresa, So Chi Wai Eric
Leukemia and Stem Cell Biology Group, Department of Hematological Medicine, King's College London, Denmark Hill campus, SE5 9NU, London, UK.
Chromosoma. 2014 Dec;123(6):545-61. doi: 10.1007/s00412-014-0482-9. Epub 2014 Aug 12.
DNA damage repair mechanisms are vital to maintain genomic integrity. Mutations in genes involved in the DNA damage response (DDR) can increase the risk of developing cancer. In recent years, a variety of polymorphisms in DDR genes have been associated with increased risk of developing acute myeloid leukemia (AML) or of disease relapse. Moreover, a growing body of literature has indicated that epigenetic silencing of DDR genes could contribute to the leukemogenic process. In addition, a variety of AML oncogenes have been shown to induce replication and oxidative stress leading to accumulation of DNA damage, which affects the balance between proliferation and differentiation. Conversely, upregulation of DDR genes can provide AML cells with escape mechanisms to the DDR anticancer barrier and induce chemotherapy resistance. The current review summarizes the DDR pathways in the context of AML and describes how aberrant DNA damage response can affect AML pathogenesis, disease progression, and resistance to standard chemotherapy, and how defects in DDR pathways may provide a new avenue for personalized therapeutic strategies in AML.
DNA损伤修复机制对于维持基因组完整性至关重要。参与DNA损伤反应（DDR）的基因突变会增加患癌风险。近年来，DDR基因中的多种多态性与急性髓系白血病（AML）发生风险增加或疾病复发相关。此外，越来越多的文献表明，DDR基因的表观遗传沉默可能促成白血病发生过程。此外，多种AML致癌基因已被证明可诱导复制和氧化应激，导致DNA损伤积累，进而影响增殖与分化之间的平衡。相反，DDR基因的上调可为AML细胞提供逃避DDR抗癌屏障的机制，并诱导化疗耐药。本综述总结了AML背景下的DDR途径，并描述了异常的DNA损伤反应如何影响AML发病机制、疾病进展和对标准化疗的耐药性，以及DDR途径中的缺陷如何为AML个性化治疗策略提供新途径。
