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首页> 外文期刊>Oncogene >Deregulation of homologous recombination DNA repair in alkylating agent-treated stem cell clones: a possible role in the aetiology of chemotherapy-induced leukaemia
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Deregulation of homologous recombination DNA repair in alkylating agent-treated stem cell clones: a possible role in the aetiology of chemotherapy-induced leukaemia

机译：烷基化剂处理的干细胞克隆中同源重组DNA修复的失调：在化学疗法诱发的白血病的病因学中的可能作用

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Chemotherapeutic regimes involving alkylating agents, such as methylators and crosslinking nitrogen mustards, represent a major risk factor for acute myeloid leukaemia. A high frequency of microsatellite instability and evidence of MSH2 loss in alkylating chemotherapy-related acute myeloid leukaemia (t-AML) suggests that DNA mismatch repair (MMR) dysfunction may be an initiating event in disease evolution. Subsequent accumulation of secondary genetic changes as a result of DNA MMR loss may ultimately lead to the gross chromosomal abnormalities seen in t-AML. Homologous recombination repair (HRR) maintains chromosomal stability by the repair of DNA double-strand breaks, and is therefore a possible target for deregulation in MMR dysfunctional t-AML. In order to test this hypothesis Msh2- proficient and -deficient murine embryonic stem (ES) cells were used to examine the effects of MMR status and methylating agent treatment on cellular expression of DNA double-strand break repair genes. HRR gene expression was significantly deregulated in Msh2 null ES cell clones compared to wild-type clones. Furthermore, some Msh2 null clones expressed high levels of Rad51 specifically, a critical component of HRR. Such Rad51 superexpressing clones were also observed when expression was determined in monocytic myeloid cells differentiated from ES cells. A deregulated HRR phenotype could be partially recapitulated in MMR-competent wild-type cells by treatment with the methylating agent, N-methyl-N-nitrosourea. Furthermore, treatment with melphalan, a leukaemogenic DNA crosslinking chemotherapy nitrogen mustard predicted to elicit HRR, selected against cells with deregulated HRR. These data suggest a t-AML mechanism whereby DNA MMR loss promotes the emergence of HRR gene superexpressing clones, with concomitant chromosomal instability. However, melphalan selection against clones with deregulated HRR suggests that persistence and expansion of unstable clones may require additional genetic alterations that promote cell survival.
机译：涉及烷化剂（例如甲基化剂和交联氮芥子）的化学疗法是急性髓细胞性白血病的主要危险因素。烷基化化疗相关的急性髓细胞性白血病（t-AML）中高频率的微卫星不稳定性和MSH2丢失的证据表明，DNA错配修复（MMR）功能障碍可能是疾病发展的起始事件。 DNA MMR丢失导致随后的继发性遗传变化积累，最终可能导致t-AML中出现明显的染色体异常。同源重组修复（HRR）通过修复DNA双链断裂来维持染色体的稳定性，因此可能是MMR功能异常的t-AML失控的可能靶标。为了检验该假设，使用了Msh2精通和缺失的小鼠胚胎干（ES）细胞来检查MMR状态和甲基化剂处理对DNA双链断裂修复基因细胞表达的影响。与野生型克隆相比，Msh2 null ES细胞克隆中的HRR基因表达显着失调。此外，一些Msh2空克隆特异性表达高水平的Rad51，这是HRR的关键组成部分。当在从ES细胞分化的单核细胞中确定表达时，也观察到了这种Rad51超表达克隆。通过使用甲基化剂N-甲基-N-亚硝基脲处理，可以在具有MMR能力的野生型细胞中部分还原失调的HRR表型。此外，用抗草甘膦（一种抗白血病的DNA交联化疗氮芥）有望引发HRR，该药物针对HRR失调的细胞进行了选择。这些数据表明了t-AML机制，其中DNA MMR丢失促进了HRR基因超表达克隆的出现，并伴有染色体不稳定。但是，针对抗HRR失调的克隆进行马法兰的选择表明，不稳定克隆的持久性和扩增可能需要其他促进细胞存活的遗传改变。

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