Sung P A, Libura J, Richardson C
Institute for Cancer Genetics, Department of Pathology, Columbia University, New York, NY 10032, USA.
DNA Repair (Amst). 2006 Sep 8;5(9-10):1109-18. doi: 10.1016/j.dnarep.2006.05.018. Epub 2006 Jun 30.
Faithful repair of chromosomal double-strand breaks (DSBs) is central to genome integrity and the suppression of genome rearrangements including translocations that are a hallmark of leukemia, lymphoma, and soft-tissue sarcomas [B. Elliott, M. Jasin, Double-strand breaks and translocations in cancer, Cell. Mol. Life Sci. 59 (2002) 373-385; D.C. van Gent, J.H. Hoeijmakers, R. Kanaar, Chromosomal stability and the DNA double-stranded break connection, Nat. Rev. Genet. 2 (2001) 196-206]. Chemotherapy agents that target the essential cellular enzyme topoisomerase II (topo II) are known promoters of DSBs and are associated with therapy-related leukemias. There is a clear clinical association between previous exposure to etoposide and therapy-related acute myeloid leukemia (t-AML) characterized by chromosomal rearrangements involving the mixed lineage leukemia (MLL) gene on chromosome band 11q23 [C.A. Felix, Leukemias related to treatment with DNA topoisomerase II inhibitors, Med. Pediatr. Oncol. 36 (2001) 525-535]. Most MLL rearrangements initiate within a well-characterized 8.3 kb region that contains both putative topo II cleavage recognition sequences and repetitive elements leading to the logical hypothesis that MLL is particularly susceptible to aberrant cleavage and homology-mediated fusion to repetitive elements located on novel chromosome partners. In this review, we will discuss the findings and implications of recent attempts to confirm this hypothesis.
染色体双链断裂（DSB）的准确修复对于基因组完整性以及抑制包括易位在内的基因组重排至关重要，易位是白血病、淋巴瘤和软组织肉瘤的一个标志[B. Elliott, M. Jasin, 《癌症中的双链断裂和易位》，《细胞与分子生命科学》59 (2002) 373 - 385；D.C. van Gent, J.H. Hoeijmakers, R. Kanaar, 《染色体稳定性与DNA双链断裂的联系》，《自然评论遗传学》2 (2001) 196 - 206]。靶向关键细胞酶拓扑异构酶II（topo II）的化疗药物是已知的DSB促进剂，并与治疗相关白血病有关。既往接触依托泊苷与治疗相关急性髓系白血病（t - AML）之间存在明确的临床关联，其特征是涉及染色体11q23带混合谱系白血病（MLL）基因的染色体重排[C.A. Felix, 《与DNA拓扑异构酶II抑制剂治疗相关的白血病》，《医学与儿科肿瘤学》36 (2001) 525 - 535]。大多数MLL重排起始于一个特征明确的8.3 kb区域，该区域既包含推定的topo II切割识别序列，也包含重复元件，从而得出一个合理的假设，即MLL特别容易发生异常切割，并通过同源介导与位于新染色体伙伴上的重复元件融合。在本综述中，我们将讨论最近为证实这一假设所做尝试的研究结果及意义。
