Genomics of Treatment -Related Acute Myelogenous Leukemia: Susceptibility Factors

该项目的长期目标是确定常见的基因变异，使患者容易患上 烷化剂相关的急性髓系白血病。与治疗相关的急性髓系白血病(t-AML)是一种致命性的、日益流行的 烷化剂化疗的并发症。有几条证据表明这其中有遗传成分 T-AML易感性。然而，t-AML的常见易感遗传因素尚未被 已确认身份。我们假设基因的种系变异在新生的AML(白血病)中发生了体细胞突变 途径基因)可能是t-AML的易感等位基因。相关的遗传变异可能包括 插入、缺失、单核苷酸多态(SNP)或更大的节段性DMA拷贝数 变种(CNV)。我们将在老鼠和人类身上使用互补的方法来确定候选 易感等位基因及其对人类t-AML的重要性。这个项目利用了几个 GAML成员的优势。在与Project 2的合作下，我们在 利用基于高密度寡核苷酸阵列的比较基因组数据鉴定CNV 杂交实验。在与项目2、4和核心D的合作下，我们正在确定 我们正在将“白血病途径”基因纳入基因关联研究。在第一次资助期间 期间，我们鉴定了几个对烷化剂相关t-AML敏感或耐药的小鼠品系。单倍型 20个亲本菌株的关联图谱表明MLF1是候选的t-AML易感因素。 正在产生同源的Mlfl零菌株来验证这个候选易感基因。我们有 大量烷基化症患者用于基因分型的累积受试者和获得性样本 T-AML和来自我们机构和外部合作者的配对对照。我们建议 以下两个目标建立在这些初步发现的基础上，以确定烷化剂相关t-DNA的遗传基础。 AML： 具体目的1.确定影响小鼠t-AML易感性的遗传因素。我们会 进行全基因组扫描，全面筛查小鼠t-AML易感基因座。我们将绘制地图 T-AML敏感株和耐药株中的CNV，CNV谱与t-AML易感性相关。高 在AIMS 1和2中发现的优先候选易感因素将使用小鼠模型进行验证。 具体目标2.我们将确定生殖系遗传变异对人类t-AML的重要性 敏感度。使用病例对照设计，我们将同时使用候选基因和全基因组 确定SNPs和CNV对人类烷化剂相关t-AML风险的影响的方法。 对易感遗传因素的识别应导致个体化治疗，降低t-T风险。 AML。

The long range goal of this project is to identify common genetic variants that predispose patients to alkylator-associated AML. Therapy-related acute myeloid leukemia (t-AML) is a lethal, increasingly prevalent complication of alkylator chemotherapy. Several lines of evidence suggest that there is a genetic component to t-AML susceptibility. However, common predisposing genetic factors for t-AML have not yet been identified. We hypothesize that germline variants of genes somatically mutated in de novo AML ("leukemia pathway" genes) may be susceptibility alleles for t-AML. The relevant genetic variants may include small insertions, deletions, single nucleotide polymorphisms (SNPs), or larger segmental DMA copy number variants (CNVs). We will utilize complementary approaches in mice and humans to identify candidate susceptibility alleles and validate their importance for human t-AML. This Project capitalizes on several strengths of GAML members. In collaboration with Project 2, we have developed expertise in the identification of CNVs using data from high-density oligonucleotide array-based comparative genomic hybridization experiments. In collaboration with Projects 2, 4 and Core D, we are identifying novel variants in "leukemia pathway" genes that we are incorporating into gene association studies. During the first funding period, we identified several mouse strains susceptible or resistant to alkylator-associated t-AML. Haplotype association mapping in 20 parental strains implicated Mlf1 as a candidate t-AML susceptibility factor. Congenic Mlfl null strains are being generated to validate this candidate susceptibility gene. We have accrued subjects and acquired specimens for genotyping from a large number of patients with alkylatorassociated t-AML and matched controls from our institution and outside collaborators. We propose the following two aims that build on these initial findings to identify the genetic basis of alkylator-associated t- AML: Specific Aim 1. We will identify genetic factors influencing t-AML susceptibility in mice. We will perform a whole genome scan to screen comprehensively for t-AML susceptibility loci in mice. We will map CNVs in t-AML susceptible and resistant strains and correlate CNV profiles with t-AML susceptibility. High priority candidate susceptibility factors discovered in Aims 1 and 2 will be validated using mouse models. Specific Aim 2. We will define the importance of germline genetic variants for human t-AML susceptibility. Using a case-control design, we will use both candidate gene and whole genome approaches to determine the impact of SNPs and CNVs on risk of alkylator-associated t-AML in humans. Identification of predisposing genetic factors should lead to personalized therapies with reduced risk of t- AML.