Epigenetic silencing of HOXA4 gene is associated with imatinib resistance, disease progression, BCR-ABL1 transcript type and smoking status among Chronic Myeloid Leukemia patients

Abstract Background We aimed to investigate the role of HOXA4 gene methylation concerning response to imatinib, and chronic myeloid leukemia (CML) progression, also investigated the impact of the type of BCR-ABL1 transcript and smoking on methylation level. Methods 45 CML patients at different clinical stages of the disease (including 20 good responses and 25 non-mutated imatinib-resistant patients) and 15 health controls were recruited. Methylation level of HOXA4 gene promoter was evaluated by Methylation Sensitive High-Resolution Melt (MS-HRM) analysis. Results There was a significant difference in the mean of HOXA4 methylation percentage between two response groups (mean = 63.8; SD = 17.79 vs mean = 47.75; SD = 14.18, P = 0. 002). HOXA4 promoter hypermethylation (51–100% methylation 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, the patients with b2a2 transcript and smokers were associated with a higher percentage of HOXA4 methylation (OR = 7.08; 95% CI, 1.80-27.79; P = 0.005, OR = 11.8; 95% CI, 2.67–52.67; P = 0.001 respectively). Conclusion Our study suggests the association of the HOXA4 gene hypermethylation with imatinib resistance and CML progression. Moreover, the BCR-ABL1 transcript type and smoking have an impact on methylation levels.