文章：

ATM功能及其与慢性淋巴细胞白血病中复发性缺失（11q22.3-23.2）的ATM基因突变的关系

ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2)

原文发布日期：2016-09-02

DOI: 10.1038/bcj.2016.69

类型: Original Article

开放获取: 是

英文摘要：

Approximately 10–20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22–23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22–23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

摘要翻译： 

约10%-20%的慢性淋巴细胞白血病（CLL）患者在治疗前存在11q22–23区段缺失，这一比例在化学免疫治疗进展后会上升至40%以上。该缺失区域包含DNA损伤应答基因——共济失调毛细血管扩张突变基因（ATM）的编码序列。残留的ATM等位基因常发生突变，提示基因功能与临床应答存在关联。为验证该可能性，我们致力于开发并验证一种检测这些患者ATM蛋白功能的方法。经电离辐射后免疫印迹检测发现，SMC1（染色体结构维持蛋白1）和KAP1（KRAB关联蛋白1）是ATM激酶的独特底物。以8例荧光原位杂交阴性CLL样本池作为标准，采用基于正态混合模型的聚类分析法对46例11q22–23缺失样本的SMC1和KAP1磷酸化水平进行检测，发现其中13例样本（28%）存在ATM功能缺陷。以基因组DNA为参照对这些样本进行ATM基因靶向测序，共检出12个体细胞突变和15个种系突变。ATM突变与功能之间未发现强相关性，因此突变状态不能作为ATM功能的指标，在治疗研发中应采用激酶活性的直接检测法。

原文链接：

ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2)