Exploring the significance of MDM2 gene promoter variants in chronic myeloid leukemia.

Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 are highly successful in chronic myeloid leukemia (CML). However, extensive interpatient variability in therapeutic responses and resistance supports the need to find new prognostic biomarkers. We have previously reported that TP53 SNP215 variant affects CML risk and clinical outcome. We aimed to evaluate the role of MDM2 genetic variants in CML susceptibility and treatment response to TKIs. We genotyped five MDM2 promoter variants (del1518, SNP309, SNP285, SNP288 and SNP344) in 135 CML patients and 136 healthy individuals. Our study showed that MDM2 variants alone or in combination had no effect on CML susceptibility. The analysis of MDM2 genotypes in relation to patients' clinical parameters revealed that individuals with SNP309 G/G genotypes were at a significantly increased risk of undergoing molecular response failure (p = 0.044). Improved overall survival was also observed for non-responders with the alternative MDM2 del1518 del allele (p = 0.017) as well as for MDM2 del1518-SNP309 combinations with alternative genotypes (p = 0.014). In addition, combinatorial analysis demonstrated that alternative MDM2 SNP309 and TP53 SNP215 genotypes together are associated with faster achievement of MR² (p = 0.029) and MMR (p = 0.042) in non-responders, suggesting a relationship with a favorable outcome. Overall, our study highlights the influence of MDM2 variants on clinical outcome, supporting that specific genotypes, alone or in combination, underlie the treatment-responsive phenotype.