PO-469 Role of promoter hypermethylation of hocT1 gene (SLC22A1) in response to imatinib of chronic myeloid leukaemia patients

IntroductionhOCT1 (Human Organic Cation Transporter 1),solute carrier transporter of SLC22 gene family,mediates influx of imatinib into cells.It is seen that intracellular imatinib uptake correlates with hOCT1 expression and may alter clinical outcome in CML.DNA methylation in promoter associated CpG islands is a powerful mechanism of gene silencing.Role of promoter hypermethylation of hOCT1 gene in CML and its effect on response to treatment with imatinib has not been studied much.Material and methods30 newly diagnosed CML patients aged 18 to 80 years were included in the study before initiation of imatinib.30 healthy volunteers participated as controls.Patients were followed up after initiation of imatinib for 6 to 12 months,haematological and molecular response were assessed.hOCT1 gene expression was studied by Real Time quantitative PCR.Promoter Methylation of hOCT1 gene was studied by Methylation Specific PCR.Results and discussionsCases were divided into 2 groups,high expression(n=15)and low expression(n=15) (median fold change=5.6).Median time to achieve complete haematological response(CHR) in high expression group was 1.93+/-0.62 months,in low expression group was 2.67+/-1.06 months(p=0.046).All 15 cases with high expression had optimal molecular response. In low expression group,out of 15,2 had optimal molecular response,6 failure,7 warning.(p=0.000)Methylation was seen in 83.33%;of CML cases whereas in only 23.33%;of controls.(p=0.001)Methylation was observed in all the 15 patients(100%) with low expression whereas amongst the high expression group,10 out of 15 patients(66.66%)were methylation positive.(p=0.042) No significant association was seen between methylation status and achievement of CHR or optimal molecular response to imatinibConclusionHigh hOCT1 gene expression is significantly associated with achievement of complete haematological and optimal molecular response to imatinib.Promoter hypermethylation of hOCT1 gene leads to silencing of gene expression.