Work

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

Year: 2018

Type: article

Abstract: // Salma A. Bargal 1 , Roya Rafiee 1 , Kristine R. Crews 2 , Huiyun Wu 3 , Xueyuan Cao 3, 4 , Jeffrey E. Rubnitz 5 , Raul C. Ribeiro 5 , James R. Downing 6 , Stanley B. Pounds 3 and Jatinder K. Lamba 1 1 Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA 2 Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA 3 Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA 4 Department of Acute and Tertiary Care, University of Tennessee Health Science Center, Memphis, TN, USA 5 Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA 6 Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA Correspondence to: Jatinder K. Lamba, email: [email protected] Keywords: cytarabine; gene expression; GWAS; pediatric acute myeloid leukemia; SNP Received: August 20, 2018 Accepted: September 08, 2018 Published: October 09, 2018 ABSTRACT 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.26163