Felix C A
Division of Oncology, Department of Pediatrics, Abramson Research Center, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):233-55. doi: 10.1016/s0167-4781(98)00139-0.
The major established cause of acute myeloid leukemia (AML) in the young is cancer chemotherapy. There are two forms of treatment-related AML (t-AML). Each form has a de novo counterpart. Alkylating agents cause t-AML characterized by antecedent myelodysplasia, a mean latency period of 5-7 years and complete or partial deletion of chromosome 5 or 7. The risk is related to cumulative alkylating agent dose. Germline NF-1 and p53 gene mutations and the GSTT1 null genotype may increase the risk. Epipodophyllotoxins and other DNA topoisomerase II inhibitors cause leukemias with translocations of the MLL gene at chromosome band 11q23 or, less often, t(8;21), t(3;21), inv(16), t(8;16), t(15;17) or t(9;22). The mean latency period is about 2 years. While most cases are of French-American-British (FAB) M4 or FAB M5 morphology, other FAB AML subtypes, myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) occur. Between 2 and 12% of patients who receive epipodophyllotoxin have developed t-AML. There is no relationship with higher cumulative epipodophyllotoxin dose and genetic predisposition has not been identified, but weekly or twice-weekly schedules and preceding l-asparaginase administration may potentiate the risk. The translocation breakpoints in MLL are heterogeneously distributed within a breakpoint cluster region (bcr) and the MLL gene translocations involve one of many partner genes. DNA topoisomerase II cleavage assays demonstrate a correspondence between DNA topoisomerase II cleavage sites and the translocation breakpoints. DNA topoisomerase II catalyzes transient double-stranded DNA cleavage and rejoining. Epipodophyllotoxins form a complex with the DNA and DNA topoisomerase II, decrease DNA rejoining and cause chromosomal breakage. Furthermore, epipodophyllotoxin metabolism generates reactive oxygen species and hydroxyl radicals that could create abasic sites, potent position-specific enhancers of DNA topoisomerase II cleavage. One proposed mechanism for the translocations entails chromosomal breakage by DNA topoisomerase II and recombination of DNA free ends from different chromosomes through DNA repair. With few exceptions, treatment-related leukemias respond less well to either chemotherapy or bone marrow transplantation than their de novo counterparts, necessitating more innovative treatments, a better mechanistic understanding of the pathogenesis, and strategies for prevention.
年轻人急性髓系白血病（AML）的主要既定病因是癌症化疗。治疗相关的AML（t-AML）有两种形式。每种形式都有与之对应的原发性AML。烷化剂导致的t-AML具有前期骨髓发育异常的特征，平均潜伏期为5至7年，且5号或7号染色体存在完全或部分缺失。风险与烷化剂的累积剂量有关。种系NF-1和p53基因突变以及GSTT1基因缺失型可能会增加风险。表鬼臼毒素和其他DNA拓扑异构酶II抑制剂导致的白血病会出现11q23染色体带处MLL基因易位，或较少见的t(8;21)、t(3;21)、inv(16)、t(8;16)、t(15;17)或t(9;22)。平均潜伏期约为2年。虽然大多数病例为法美英（FAB）M4或FAB M5形态，但也会出现其他FAB AML亚型、骨髓增生异常综合征（MDS）、急性淋巴细胞白血病（ALL）和慢性粒细胞白血病（CML）。接受表鬼臼毒素治疗的患者中有2%至12%发生了t-AML。这与较高的表鬼臼毒素累积剂量无关，且尚未确定遗传易感性，但每周或每两周一次的给药方案以及之前使用L-天冬酰胺酶可能会增加风险。MLL基因的易位断点在一个断点簇区域（bcr）内分布不均，MLL基因易位涉及许多伙伴基因中的一个。DNA拓扑异构酶II切割试验表明DNA拓扑异构酶II切割位点与易位断点之间存在对应关系。DNA拓扑异构酶II催化短暂的双链DNA切割和重新连接。表鬼臼毒素与DNA和DNA拓扑异构酶II形成复合物，减少DNA重新连接并导致染色体断裂。此外，表鬼臼毒素代谢会产生活性氧和羟基自由基，这些物质可能会产生无碱基位点，是DNA拓扑异构酶II切割的有效位置特异性增强剂。一种关于易位的推测机制是由DNA拓扑异构酶II导致染色体断裂，以及通过DNA修复使来自不同染色体的DNA自由末端发生重组。除了少数例外情况，治疗相关的白血病对化疗或骨髓移植的反应比原发性白血病更差，这就需要更具创新性的治疗方法、对发病机制有更好的机制理解以及预防策略。
