Genomics of Treatment -Related Acute Myelogenous Leukemia: Susceptibility Factors

该项目的长期目标是确定使患者易患以下疾病的常见遗传变异： 烷化剂相关AML。治疗相关性急性髓细胞白血病（t-AML）是一种致命的， 烷化剂化疗的并发症。有几条证据表明， t-AML易感性的关系然而，t-AML的常见易感遗传因素尚未得到证实。 鉴定我们假设，在新生AML（“白血病”）中， “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小的 插入、缺失、单核苷酸多态性（SNP）或较大的DNA片段拷贝数 变异体（CNVs）。我们将在小鼠和人类中利用互补方法来识别候选人。 易感性等位基因，并验证其对人类t-AML的重要性。该项目利用了几个 GAML成员的优势。通过与项目2合作，我们开发了以下方面的专业知识： 使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的合作中，我们正在确定新的变异， “白血病途径”基因，我们正在纳入基因关联研究。在第一次融资期间 在此期间，我们鉴定了几种对烷化剂相关t-AML敏感或耐药的小鼠品系。单体型 在20个亲本菌株中的关联作图暗示Mlf 1是候选t-AML易感因子。 正在生成同源Mlfl无效菌株以验证该候选易感基因。我们有 招募受试者并从大量烷基化相关患者中获取样本进行基因分型 t-AML和来自我们机构和外部合作者的匹配对照。我们建议 以下两个目标是建立在这些初步发现的基础上，以确定烷化剂相关的t- AML： 具体目标1。我们将确定影响小鼠t-AML易感性的遗传因素。我们将 进行全基因组扫描，全面筛查小鼠中的t-AML易感基因座。我们将绘制 t-AML敏感和耐药菌株中的CNV以及CNV谱与t-AML敏感性的相关性。高 在目标1和2中发现的优先候选易感因子将使用小鼠模型进行验证。 具体目标2。我们将定义人类t-AML的生殖系遗传变异的重要性 易感性使用病例对照设计，我们将使用候选基因和全基因组 确定SNP和CNV对人类烷化剂相关t-AML风险的影响的方法。 易感遗传因素的识别应导致个性化治疗，降低t- 急性髓细胞白血病

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.