The Role of Association of Tyrosine Kinase Domain Mutation (T315I) with Programmed Death Ligand-1 in Resistant to Imatinib Mesilate in Sudanese Patients with Chronic Myeloid Leukemia

Abstract

DL-1) acts an inhibitory molecule for T cells leading to suppressing T-cell and decrease ability of t-cell to kill tumor cells. However, Chronic Myeloid Leukemia cells exploit such molecules to escape immune surveillance. Objectives: To analyze the association between Tyrosine Kinase Domain Mutation (T315I) and Programmed Death Ligand-1 in resistant to Imatinib Mesilate in Sudanese patients with Chronic Myeloid Leukemia. Methodology: A cross-sectional case control study, a total of 150 participants, 100 patients with Chronic Myeloid Leukemia in chronic phases of disease, (68 males, 32 females), were conducted from Khartoum Oncology Hospital-Khartoum- Sudan during (2018-2023). All patients treated with Imatinib Mesilate for at least 6 months, with IM dose of 600 mg, while 50 apparently healthy controls (30 males and 20 females). Their mean ages in case group were (54.2±12.4) years, males (54.2±13.9 years) where the females (54.1±11.9 years). their mean ages in control group were (46.8±9.1) years, males (46.8±8.4 years) where the females (46.8±8.49 years). Blood samples were collected from all participants. The analysis of the plasma levels of programmed cell death ligand-1 (PDL1) was done by sandwich ELISA test using commercially available kits, the results was confirmed by repeating two times take the average readings. Also, the BCRABLT315I gene mutation was analyzed using molecular techniques (Real Time qPCR). Result: results of the present study showed that the mean plasma levels of PDL-1 in Sudanese patients with Chronic Myeloid Leukemia resistant to Imatinib Mesilate was significantly increased (0.613ng/ml) when compared to healthy control group (0.336 ng/ml). The prevalence of BCR-ABLT315I mutation in Sudanese patients with Chronic Myeloid Leukemia resistant to Imatinib Mesilate was 11%. A statistical analysis revealedIV the correlation between the plasma levels PDL-1 and mutation status in Sudanese patients with Chronic Myeloid Leukemia resistant to Imatinib Mesilate, showed a positive correlation between T315I mutation and plasma levels PDL-1 concentrations, with correlation coefficient (0.3713) indicates moderate correlation. The present study showed cut-off value result, the median plasma level of PDL-1 in CML patients was significant increase were compared to healthy controls (0.595ng/ml vs 0.335ng/ng/ml). Also, the cutoff value result of the median the patients with positive BCR-ABLT315I mutation was a significant increase were compared to those negative BCR-ABLT315I mutation (0.718 ng/ml vs 0.592 ng/ml). In addition, the cut-off values derived from the ROC curve, the plasma levels of PD-L1 was significantly increased in CML patients, showed high accuracy (0.877). At best cut off value (>0.593ng/ml), sensitivity was (100%), specificity was (66.9%) and increased plasma levels of PD-L1 was significantly increase in positive T315I mutation patients showed high accuracy (0.808). At best cut off value (>0.685ng/ml), sensitivity was (63.6%), specificity was (87.6%). Conclusion: our results indicate that the patients with chronic myeloid leukemia Imatinib Mesilate resistant had higher plasma levels of PDL-1 in their blood compared to the control group and the patients with a positive BCR-ABLT315I mutation were found to had higher levels of plasma levels of PDL-1 than BCR-ABT315I-mutation-negative patients. Key words: Programmed Death Ligand-1 (PDL-1), Chronic Myeloid Leukemia (CML), BCR-ABLT315I mutation, Imatinib and ELISA.V