Genome scan implicates adhesion biological pathways in secondary leukemia
Genome scan implicates adhesion biological pathways in secondary leukemia
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DOI：
10.1038/sj.leu.2404885
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发表时间：
2007-10-01
期刊：
影响因子：
11.4
通讯作者：
Relling, M. V.
中科院分区：
文献类型：
--
作者：
Hartford, C.;Yang, W.;Relling, M. V.
足叶乙甙诱导白血病伴MLL易位的遗传危险因素仍不清楚。为了确定继发性白血病的遗传危险因素和新的特征，我们分析了116 204个单核苷酸多态性（SNPs）在生殖细胞和配对的白血病细胞DNA从13个继发性白血病/骨髓增生异常病例和生殖细胞DNA从13个匹配和156个不匹配的对照，所有与急性淋巴细胞白血病治疗依托泊苷。我们分析了来自部分重叠队列的全局基因表达。在大多数情况下，没有单个位点发生改变。我们在白血病原始细胞中发现了81个杂合性缺失（洛）区域和309个SNP，其等位基因频率在病例组和对照组中存在差异。候选基因的优先顺序是基于其SNP或表达将病例与对照区分开的基因，或来自13例病例的生殖细胞与配对原始细胞DNA中显示洛缺失或拷贝数变化的基因。三种生物学途径被改变：粘附、Wnt信号传导和肌动蛋白调节。在15个HapMap细胞系中使用基因组扫描对依托泊苷诱导的致白血病MLL嵌合融合进行验证实验，也涉及参与粘附的基因，粘附是与从头白血病发生相关的过程。独立的临床流行病学和体外全基因组方法汇聚在一起，以确定可能导致治疗诱导白血病的新途径。
The genetic risk factors for etoposide-induced leukemia with MLL translocations remain largely unknown. To identify genetic risk factors for and novel characteristics of secondary leukemia, we profiled 116 204 single nucleotide polymorphisms ( SNPs) in germline and paired leukemic cell DNA from 13 secondary leukemia/myelodysplasia cases and germline DNA from 13 matched and 156 unmatched controls, all with acute lymphoblastic leukemia treated with etoposide. We analyzed global gene expression from a partially overlapping cohort. No single locus was altered in most cases. We discovered 81 regions of loss of heterozygosity (LOH) in leukemic blasts and 309 SNPs whose allele frequencies differed in cases vs controls. Candidate genes were prioritized on the basis of genes whose SNPs or expression differentiated cases from controls or showed LOH or copy number change in germline vs paired blast DNA from the13 cases. Three biological pathways were altered: adhesion, Wnt signaling and regulation of actin. Validation experiments using a genome scan for etoposide-induced leukemogenic MLL chimeric fusions in 15 HapMap cell lines also implicated genes involved in adhesion, a process linked to de novo leukemogenesis. Independent clinical epidemiologic and in vitro genome-wide approaches converged to identify novel pathways that may contribute to therapyinduced leukemia.