The long range goal of this project is to identify common genetic variants that predispose patients toalkylator-associated AML. Therapy-related acute myeloid leukemia (t-AML) is a lethal, increasingly prevalentcomplication of alkylator chemotherapy. Several lines of evidence suggest that there is a genetic componentto t-AML susceptibility. However, common predisposing genetic factors for t-AML have not yet beenidentified. We hypothesize that germline variants of genes somatically mutated in de novo AML ('leukemiapathway' genes) may be susceptibility alleles for t-AML. The relevant genetic variants may include smallinsertions, deletions, single nucleotide polymorphisms (SNPs), or larger segmental DMA copy numbervariants (CNVs). We will utilize complementary approaches in mice and humans to identify candidatesusceptibility alleles and validate their importance for human t-AML. This Project capitalizes on severalstrengths of GAML members. In collaboration with Project 2, we have developed expertise in theidentification of CNVs using data from high-density oligonucleotide array-based comparative genomichybridization 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 fundingperiod, we identified several mouse strains susceptible or resistant to alkylator-associated t-AML. Haplotypeassociation 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 haveaccrued subjects and acquired specimens for genotyping from a large number of patients with alkylatorassociatedt-AML and matched controls from our institution and outside collaborators. We propose thefollowing 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 willperform a whole genome scan to screen comprehensively for t-AML susceptibility loci in mice. We will mapCNVs in t-AML susceptible and resistant strains and correlate CNV profiles with t-AML susceptibility. Highpriority 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-AMLsusceptibility. Using a case-control design, we will use both candidate gene and whole genomeapproaches 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.
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