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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&lt;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&lt;0.0001), ii) gene-expression with cytarabine sensitivity (p&lt;0.05), and iii) genotype with gene-expression (p&lt;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.

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