PO-470 hOCT1 gene polymorphism M420del is associated with decreased response to imatinib in CML patients and amp; its effect is counteracted by M408V polymorphism

Abstract

IntroductionHuman organic cation transporter1 (hOCT1,SLC22A1),an influx transporter,is responsible for the uptake of Imatinib into chronic myelod leukaemia (CML)cells. Some patients fail to achieve optimal molecular response to Imatinib, defined as major molecular response (MMR) i.e. BCR-ABL 1≤0.1% within 12 months of therapy. Variation in clinical response to Imatinib has been observed with two nonsynonymous SNPs in hOCT1 gene, namely M420del and M408V in some populations.Material and methods30 newly diagnosed BCR-ABL positive CML patients in chronic phase,and 30 healthy control subjects, all ethnic Indians, were recruited in the study. M420del and M408V SNPs were examined by allele specific PCR(AS-PCR) in DNA from PBMCs.After initiation of imatinib therapy, haematological response was monitored at regular intervals, and molecular response (BCR-ABL1/ABL1 ratio) assessed after 6 or 12 months.Results and discussionsMinor allele frequencies for M420del were 0.18 and 0.1 in CML patients and controls; for M408V 0.4 and 0.27 respectively, closely paralleling those reported in western population.No significant association between different genotypes of M420del and M408V was observed with either time to achieve complete haematological response (CHR) (p=0.341 for both SNPs),or presence of optimal/sub-optimal molecular responses(p=0.125, 0.629 for M420del and M408V respectively).To analyse the combined effect of these two SNPs, CML cases were divided into 4 groups.Patients with mutant (homo/heterozygous) M420del and wild type homozygous M408V, failed to achieve an optimal molecular response to imatinib, unlike those with mutant genotypes (homo/heterozygous) for both SNPs (p=0.02).ConclusionMutant M420del allele may be linked to poor outcome of imatinib treatment in CML,however simultaneous presence of mutant M408V allele appears to circumvent this effect.These SNPs in hOCT1 gene occur at reasonable frequencies in Indian population, to be of clinical interest as predictors of response to imatinib in CML.