Genomics of AML: Whole Genome Resequencing

“AML基因组学”PPG的长期目标是确定导致AML的遗传变化。 开发急性髓细胞白血病的分子诊断工具， 疾病分层，并确定新的候选基因的靶向治疗方法。我们打算 鉴定负责疾病的起始和进展的体细胞突变（项目1，2， 和4和核心C），以及与复发和化疗耐药性相关的遗传变化 （项目3）。我们还打算确定导致AML易感性增加的机制， 已接受烷化剂治疗（项目5）。为了实现这些目标，病理材料和临床数据 在核心A中收集来自AML患者的样本，并将患者样本储存并进行基于阵列的分析。 在核心B中进行基因组筛选，为了以无偏的方式发现AML基因组中的所有突变，我们 建议对来自10个患有AML的个体的AML细胞和正常皮肤细胞的整个基因组进行测序， FAB Ml AML在赠款续期（项目1）。我们现在已经完成了1例病例的这一目标 （Nature 456：66-72，2008），并将在第一年完成第二和第三个M1 AML基因组 周期由于用DNA测序法获得的DNA序列的成本和质量有了显著的提高， “下一代”测序平台，我们要求90万美元（SOOK/年）的补充资金， 2-4年，以进一步加快项目1的工作。如果获得补充资金，我们将 序列7，第2年新的细胞遗传学正常的AML Ml基因组。在第三年，我们将能够 对10个携带t（15;17）作为唯一细胞遗传学异常的M3 AML基因组进行测序。以来 由这种易位引起的PML-RARA融合蛋白已知会引发M3 AML，我们将能够 对比这两种截然不同的、定义明确的AML亚型中发现的突变类型。反洗钱 第4年选择的基因组将由第2年和第3年的结果指导， 如果费用继续下降，将涉及数十个额外的精心挑选的案件。所有的DNA样本 研究所需的基因组序列目前已获得并同意进行全基因组测序。

The long-term goals ofthe "Genomics of AML" PPG are to define the genetic changes responsible forthe developmentof acute myeloid leukemia in order to create improved molecular tools for diagnosis and disease stratification, and to identify new candidate genes for targeted therapeutic approaches. We intend to identify somatic mutations that are responsible forthe initiation and progression of disease (Projects 1, 2, and 4 and Core C), and the genetic changes associated with relapse and chemotherapeutic resistance (Project 3). We also intend to identify mechanisms leading to increased AML susceptibility in patients who have received alkylator therapy (Project 5). To accomplish these aims, pathologic material and clinical data from AML patients is collected in Core A, and patient samples are banked and subjected to array-based genomic screens ih Core B, To discover all ofthe mutations in AML genomes in an unbiased fashion, we proposed to sequence the entire genomes of the AML cells and normal skin cells from 10 individuals with FAB Ml AML at the renewal ofthe grant (Project 1). We have now accomplished this goal for 1 case (Nature 456:66-72, 2008), and will finish a second and third M1 AML genome during year 1 ofthe grant cycle. Because of remarkable improvements in the cost and quality of DNA sequence obtained with 'next generation' sequencing platforms, we request $900,000 (SOOK/year) in supplemental funds in years 2-4 to further accelerate the work in Project 1. If supplemental funds are granted, we will sequence 7,new cytogenetically normal AML Ml genomes in year 2. In year 3, we will be able to sequence 10 total M3 AML genomes bearing t(15;17) as the sole cytogenetic abnormality. Since the PML-RARA fusion protein caused by this translocation is known to initiate M3 AML, we will be able to contrast the kinds of mutations found in these two very distinct, very well defined AML subtypes. The AML genomes selected for year 4 will be directed by the results of years 2 and 3, and could potentially involve dozens of additional carefully selected cases if costs continue to fall. All of the DNA samples required for the study are currently available and consented for whole genome sequencing