Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion
Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion
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DOI：
10.1200/jco.2007.11.2649
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发表时间：
2007-12-01
影响因子：
45.3
通讯作者：
Stankovic, Tatjana
中科院分区：
文献类型：
--
作者：
Austen, Belinda;Skowronska, Anna;Stankovic, Tatjana
目的共济失调毛细血管扩张症突变（ATM）基因位于染色体11 q上，该区域的缺失在B细胞慢性淋巴细胞白血病（CLL）中很常见。我们的目的是确定是否CLL肿瘤与染色体11 q缺失可能被分为两个亚组的基础上剩余的ATM等位基因的状态。方法剩余的ATM等位基因的序列被确定在72个CLL与11 q缺失。这是相关的细胞反应，辐射或细胞毒性药物暴露在体外和clinical outcome.Results我们表明，剩余的ATM等位基因突变的CLLs的36%与11 q缺失，这些白血病表现出受损的细胞反应，辐射或细胞毒性药物暴露在体外。第二个ATM等位基因的失活与患者生存率的降低相关，超过了11q缺失的存在（P = 0.0283）。此外，我们证明ATM突变可能会出现在一个11 q缺失的亚克隆的进化过程中，并与其expanding.ConclusionCLL与11 q缺失可分为两个亚组的基础上的剩余ATM等位基因的完整性。由于双等位基因ATM缺陷，ATM功能完全丧失的患者对体外细胞毒性化疗药物的反应有缺陷，临床结局较差。ATM突变亚克隆可以在个体的疾病过程中发展，并引起11 q缺失亚克隆的额外扩增。
Purpose The ataxia telangiectasia mutated (ATM) gene is located on chromosome 11q and loss of this region is common in B-cell chronic lymphocytic leukemia (CLL). Our aim was to determine if CLL tumors with a chromosome 11q deletion might be divided into two subgroups based on the status of the remaining ATM allele.Methods The sequence of the residual ATM allele was determined in 72 CLLs with an 11q deletion. This was related to the cellular response to irradiation or cytotoxic drug exposure in vitro and clinical outcome.Results We show that the residual ATM allele is mutated in 36% of CLLs with an 11q deletion and that these leukemias demonstrate an impaired cellular response to irradiation or cytotoxic drug exposure in vitro. Inactivation of the second ATM allele was associated with a reduction in patient survival beyond that already dictated by the presence of an 11q deletion (P =.0283). Furthermore, we demonstrate that ATM mutations may arise during the evolution of an 11q deleted subclone and are associated with its expansion.Conclusion CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.