Epigenetic silencing of DDIT3 gene and its relationship with imatinib resistance, disease progression and smoking status among patients with chronic myeloid leukemia

Background:The evolution of resistance to imatinib and disease progression are multifactorial events in CML patients.These events are not only determined by BCR-ABL1 dependent pathway but also are involved a number of other genetic and epigenetic aberrations including DNA methylation.We aimed to investigate the role of DDIT3 (DNA-damage-inducible transcript 3) gene methylation in relation to respose to imatinib, CML progression, and also investigate the impact of the smoking on methylation level.Materials and methods: 50 CML patients at different clinical stages of the disease (including 20 good response and 30 non-mutated imatinib resistant patients) and 15 health control were recruited for methylation levels evaluation of promoter DDIT3 gene by MS-HRM (Methylation Sensitive High Resolution Melt) analysis.Results: There was significant difference in the mean (standard deviation) of DDIT3 methylation percentage between two response groups (63.817.79vs 47.7514.18,P=0.002).DDIT3 promoter hypermethylation in 51-100% level indicated a higher risk for progression to advance phase (OR= 5.75; 95% CI: 1.40-23.49;P= 0.01) and imatinib resistance (OR= 8.5; 95% CI: 1.96-36.79;P= 0.004).Importantly, smokers were associated with a higher percentage of DDIT3 methylation (OR= 11.8; 95% CI, P=0.001).Conclusion: Our findings indicated that hypermethylation of DDIT3 gene is associated with imatinib resistance, CML progression and smoking.Further investigations on a more number is needed to confirm of these results that could be suggest as potential biomarker of disease progression and resistance to imatinib.