Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia
Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia
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DOI：
10.1158/0008-5472.can-08-0101
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发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Irving, Julie A. E.
中科院分区：
文献类型：
--
作者：
Case, Marian;Matheson, Elizabeth;Irving, Julie A. E.
RAS-RAF-促分裂原活化蛋白激酶/细胞外信号调节激酶（ERK）激酶（MEK）-ERK信号级联的失调通常是由编码影响该途径活性的蛋白质（包括NRAS、KRAS 2、FLT 3、PTPN 11和BRAF）的基因的体细胞突变引起的。我们报告的第一个全面的突变筛选这些基因的关键外显子在一个大队列的急性淋巴细胞白血病（ALL）的情况下，在诊断（n = 86），并在一个更选定的队列在疾病复发（n = 47），使用敏感的变性高效液相色谱法。我们发现，体细胞突变，失调的途径构成了最常见的遗传畸变在儿童ALL（cALL），被发现在35%的诊断和25%的复发样本。在匹配的呈现/复发对中，使用等位基因特异性PCR，复发时占优势的突变可以显示在诊断时以非常低的水平存在，从而暗示突变的克隆在疾病进展中。重要的是，在原始样本中，我们发现突变与活化的ERK相关，并且在一些患者中显示出对MEK-ERK抑制剂的差异细胞毒性。目前正在进行临床试验的通路抑制剂可能是cALL的一种新的治疗选择，特别是在复发时。
Deregulation of the RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK signaling cascade is often caused by somatic mutations in genes encoding proteins which influence the activity of this pathway and include NRAS, KRAS2, FLT3, PTPN11, and BRAF. We report the first comprehensive mutational screen of key exons of these genes in a large cohort of unselected acute lymphoblastic leukemia (ALL) cases at diagnosis (n = 86) and in a more selected cohort at disease recurrence (n = 47) using the sensitive method of denaturing high-performance liquid chromatography. We show that somatic mutations that deregulate the pathway constitute one of the most common genetic aberrations in childhood ALL (cALL), being found in 35% of diagnostic and 25% of relapse samples. In matched presentation/relapse pairs, mutations predominating at relapse could he shown to be present at very low levels at diagnosis using allele-specific PCR, thus implicating the mutated clone in disease progression. Importantly, in primary samples, we show that mutations are associated with activated ERK and differential cytotoxicity to MEK-ERK inhibitors was shown for some patients. Inhibitors of the pathway, which are currently undergoing clinical trial, may be a novel therapeutic option for cALL, particularly at relapse.