Background: Chronic myeloid leukemia (CML) is a cancer caused by uncontrolled growth of myeloid cells in the bone marrow. Tyrosine kinase inhibitors (TKIs) like imatinib have revolutionized treatment, but resistance remains a challenge, possibly due to genetic variations. Specifically, the 3435TT genotype has been linked to lower event-free survival in CML and B-cell acute lymphoblastic leukemia (B-ALL) patients, with multivariate analysis identifying it as an independent risk factor for imatinib resistance in CML cases. Therefore, the aim of our study was to evaluate the association of multidrug resistance mutation 1 (MDR1) C3435T (rs1045642) and G2677T (rs2032581) gene variations with the CML susceptibility and resistance to imatinib mesylate.

Methods: In this case-control study, 50 CML patients and 50 healthy controls from the Saudi population were recruited. DNA was extracted from peripheral blood samples, and the MDR1 C3435T (rs1045642) and G2677T (rs2032581) genotyping were analyzed by using PCR-RFLP analysis to assess the correlation among MDR1 genotypes and the risk of CML.

Results: It has been found that MDR1 C3435T (rs1045642) variation was statistically significant (p = 0.035) between CML patients and healthy controls. In addition, strong association was reported for MDR1 G2677T (rs2032581) variation (p = 0.044) between the CML patients and healthy controls. The results of MDR1 (rs1045642) show that individuals with the TT genotype were significantly associated with risk of developing CML as evidenced by the odds ratio (OR) is 6.75 (95% CI: 1.3181 to 34.5662), and p = 0.021. Similarly in dominant model, CT + TT genotypes vs CC genotype was significantly associated with risk of developing CML as evidenced by the odds ratio is 2.25 (95% CI: 1.010 to 5.008), p = 0.047. The allelic comparison highlighted a strong association of the MDR1-T allele with CML risk (OR = 2.26, p = 0.009). Under the codominant model, the MDR1 rs2032581-GT genotype showed a substantial link with CML susceptibility, evidenced by an OR of 2.56, p = 0.041. Additionally, the MDR1-TT genotype indicated increased susceptibility with an OR of 3.16, p = 0.049. The allelic comparison highlighted a strong association of the MDR1-T allele with CML risk OR = 2.04, p = 0.014.

Conclusion: It was concluded that MDR1 rs2032581 G>T MDR1 rs1045642 C>T polymorphisms might be a risk factor for imatinib resistance in Saudi CML patients. Significant associations were reported between MDR1 genotypes and molecular responses to imatinib and advanced stage of the disease. Determination of MDR1 polymorphisms MDR1 rs2032581 G>T MDR1 rs1045642 C>T might be useful in response prediction to therapy with imatinib in patients with CML.