ABCB1 (MDR1, P-Glycoprotein) C3435T Gene Polymorphism and its Possible Association with Chronic Myeloid Leukemia Prognosis

Adenosine triphosphate-binding cassette B1 (MDR1multiple drug resistance gene1), a drug transporter gene encodes a transmembrane glycoprotein (P-gp), which functions as an efflux pump for various structurally unrelated anticancer agents and toxins. Our main objective is to study MDR1 gene polymorphism at C3435T in chronic myeloid leukemia (CML) to understand its association with development and response to drug (Imatinib) treatment. The present study comprises of 150 CML cases and 150 age and sex matched controls. MDR1 C3435T polymorphism was analyzed through polymerase chain reaction followed by restriction enzyme digestion (PCR-RFLP). The MDR1 genotype distribution revealed elevated frequency of TT genotype in CML patients (34%) when compared to controls (28.67%). Within the disease group, T allele frequency (0.59) was elevated as compared to C allele frequency (0.41). The functional significance of MDR1 C3435T polymorphism with respect to Imatinib (P-gp substrate) treatment was also studied in terms of hematological and cytogenetic responses. Patients without hematological response had higher frequency of TT genotype (52.63%) as compared to those with major (32.23%) or minor (20%) hematological response. Whereas patients without cytogenetic response had higher frequency of CC genotype (27.03%) compared to those with major (15.15%) or minor (10.64%) cytogenetic response When the data was compared in relation to combination of both types of responses, the frequency of CC genotype was increased significantly in cytogenetic nonresponders and the increase was found to be inversely proportional to the degree of cytogenetic response. This could be attributed to over expression of P-gp in individuals with CC genotype that might have resulted in increased efflux of Imatinib, a P-gp substrate leading to drug resistance. The present study indicates the possible association of MDR1 (C3435T) polymorphism with increased risk for development of CML in T allele carriers and poor drug response in C allele carriers.