Loss of heterozygosity and somatic mutations of the Glucocorticoid receptor gene are rarely found at relapse in pediatric acute lymphoblastic leukemia but may occur in a subpopulation early in the disease course
Loss of heterozygosity and somatic mutations of the Glucocorticoid receptor gene are rarely found at relapse in pediatric acute lymphoblastic leukemia but may occur in a subpopulation early in the disease course
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DOI：
10.1158/0008-5472.can-05-1227
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发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Hall, AG
中科院分区：
文献类型：
--
作者：
Irving, JAE;Minto, L;Hall, AG
糖皮质激素是治疗儿童急性淋巴细胞白血病（ALL）的关键，在大多数儿童中具有显著的抗白血病作用。然而，临床耐药是一个重大问题。尽管细胞系模型暗示糖皮质激素受体（GR）基因的体细胞突变和杂合性缺失（LOH）是体外糖皮质激素耐药的一种机制，但这种机制与ALL患儿临床耐药的相关性尚不清楚。在一个复发all的大队列中进行了GR基因所有编码外显子的突变筛选和LOH分析。我们表明，体细胞突变和GR的LOH很少导致ALL患儿疾病复发。然而，我们报告了第二例ALL的GR体细胞突变，涉及8外显子29 bp的缺失，导致部分配体结合域的缺失。没有证据表明存在野生型等位基因。等位基因特异性PCR在发病后第28天检测到突变克隆，在整个病程中一直保持低水平，直到几年后复发。我们假设，在初始诊断时存在于白血病亚克隆中的突变等位基因在糖皮质激素诱导缓解期间被选中，并促成了糖皮质激素抗性细胞群的出现。
Glucocorticoids are pivotal in the treatment of children with acute lymphoblastic leukemia (ALL) and have significant antileukemic effects in the majority of children. However, clinical resistance is a significant problem. Although cell line models implicate somatic mutations and loss of heterozygosity (LOH) of the glucocorticoid receptor (GR) gene as a mechanism of in vitro glucocorticoid resistance, the relevance of this mechanism as a cause of clinical resistance in children with ALL is not known. Mutational screening of all coding exons of the GR gene and LOH analyses were done in a large cohort of relapsed ALL. We show that somatic mutations and LOH of the GR rarely contribute to relapsed disease in children with ALL. However, we report the second case of ALL with a somatic mutation of the GR involving a 29-bp deletion in exon 8 and resulting in a truncated protein with loss of part of the ligand-binding domain. There was no evidence of a remaining wild-type allele. Allele-specific PCR detected the mutated clone at day 28 after presentation, which persisted at a low level throughout the disease course before relapse several years later. We hypothesize that the mutated allele present in a leukemic subclone at initial diagnosis was selected for during remission induction with glucocorticoids and contributed to the emergence of a glucocorticoid-resistant cell population.