Hypermethylation of HOXA4 Gene Promoter and Its Potential Association with Disease Progression, Imatinib Resistance, High Sokal Score Risk, and Smoking among Chronic Myeloid Leukemia Patients

The evolution of resistance to imatinib and disease progression are multifactorial events in chronic myeloid leukemia (CML) patients. In addition to the BCR-ABL1 dependent pathway, a number of other genetic and epigenetic aberrations, including DNA methylation, are also involved in the creation of these events. We aimed to investigate the role of HOXA4 gene methylation concerning response to imatinib, CML progression, and the impact of sokal score risk, BCR-ABL1 transcript type and smoking on methylation level. 80 CML patients (including 30 good responses and 50 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. There was a significant difference in the mean of HOXA4 methylation level between two response groups (mean = 65.6; SD = 18.22 vs. mean = 48.2; SD = 12.1, P < 0.0001). HOXA4 promoter hypermethylation (75–100% methylation level) indicated a higher risk for progression to advance phase (OR = 4.06; 95% CI: 1.19–13.84; P = 0.02) and imatinib resistance (OR = 3.26; 95% CI: 1.26–8.43; P = 0.01). Importantly, HOXA4 hypermethylation was associated with b2a2 transcript type, smoke and high sokal risk score (OR = 2.78; 95% CI, 1.11–6.94; P = 0.02, OR = 3.47; 95% CI, 1.37–8.78; P = 0.008, OR = 4.14; 95% CI, 1.57–10.95; P = 0.004 respectively). Our study suggests that HOXA4 gene hypermethylation could be supposed as an epigenetic biomarker for prognosis of imatinib resistance and CML progression. Moreover, risk of HOXA4 hypermethylation is associated with the BCR-ABL1 transcript type, high risk score and smoking.