Genome-wide association analysis identifies SNPs predictive of in vitro leukemic cell sensitivity to cytarabine in pediatric AML

Cytarabine has been an integral part of acute myeloid leukemia (AML) chemotherapy for over four decades. However, development of resistance and high rates of relapse is a significant impediment in successfully treating AML. We performed a genome-wide association analysis (GWAS) and identified 113 (83 after adjusting for Linkage Disequilibrium) SNPs associated with in vitro cytarabine chemosensitivity of diagnostic leukemic cells from a cohort of 50 pediatric AML patients (p<10(-4)). Further evaluation of diagnostic leukemic cell gene-expression identified 19 SNP-gene pairs with a concordant triad of associations: i)SNP genotype with cytarabine sensitivity (p<0.0001), ii) gene-expression with cytarabine sensitivity (p<0.05), and iii) genotype with gene-expression (p<0.1). Two genes from SNP-gene pairs, rs1376041-GPR56 and rs75400242-IGF1R, were functionally validated by siRNA knockdown in AML cell lines. Consistent with association of rs1376041 and gene-expression in AML patients siRNA mediated knock-down of GPR56 increased cytarabine sensitivity of AML cell lines. Similarly for IGF1R, knockdown increased the cytarabine sensitivity of AML cell lines consistent with results in AML patients. Given both IGF1R and GPR56 are promising drug-targets in AML, our results on SNPs driving the expression/function of these genes will not only enhance our understanding of cytarabine resistance but also hold promise in personalizing AML for targeted therapies.