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 (63.8±17.79 vs 47.75±14.18, 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, 2.67-52.67; 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.