Influence of genetic variants of oxidative stress related genes on prognosis and therapy response in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of BCR-ABL1 oncogene. Oxidative stress conditions are crucial in tumor development and progression. The NRF2, codified by NFE2L2 gene, plays a central role in redox balance, promoting the transcription of cytoprotective and antioxidant genes such as SOD2, GPX1 and CAT. The action of this transcription factor is regulated by KEAP1. Alterations in these genes, either due to somatic mutations or genetic variants (SNV), have been associated with the development, prognosis, and therapeutic response in cancer. This work evaluated the influence of polymorphisms in genes associated with oxidative stress (NFE2L2, KEAP1, SOD2, GPX1, and CAT) in prognosis and treatment response with tyrosine kinase inhibitors (TKI) in CML patients. In 194 CML samples, nine genetic variants in NFE2L2 (rs6721961, rs4893819, rs35652124, rs6706649 and rs13001694), KEAP1 (rs113540846), SOD2 (rs4880), GPX1 (rs1050450) and CAT (rs1001179) were genotyped by PCR based assays. The association of these genetic variants with clinical-laboratory characteristics were assessed by Fisher’s test, logistic regression, and Kaplan-Meier curves, considering a p<0.05. The results obtained showed that patients with G allele on GPX1 rs1050450 and KEAP1 rs113540846 variants have an approximately 2-fold and 31-fold higher probability of being TKI resistant, respectively. In TKI-resistant group, patients with CT genotype in NFE2L2 rs4893819 variant were more likely to need three or more lines of treatment (OR=5.60, 95%CI 1.22-25.75, p=0.027). An important factor for TKI response is BCR-ABL1 mutational status, and we found that individuals with AG genotype in NFE2L2 rs13001694 present, approximately 9x more risk of mutation on this fusion gene. Moreover, patients heterozygous for the NFE2L2 rs4893819 (CT genotype) and SOD2 rs4880 (AG genotype) variants have faster disease progression [NFE2L2: hazard ratio (HR)=7.84, 95% CI 1.82-29.93, p=0.020; SOD2: HR=7.19, 95% CI 1.62-31.96, p=0.035] comparing with other genotypes. While the GG genotype of the NFE2L2 rs13001694 variant has a 2-fold lower overall survival than other patients (HR=11.86, 95% CI 1.39-1000.7, p=0.023). Additionally, we also observed an association between haplotypes and genotypic profile with CML prognosis. In conclusion, our results suggest that genetic variants in genes associated with the redox state might be important factors in the prognosis, survival, and therapy response in CML patients.