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

Area of Science:

• Genetics
• Oncology
• Pharmacogenomics

Background:

• Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 are effective for chronic myeloid leukemia (CML).
• Interpatient variability in TKI response and resistance necessitates novel prognostic biomarkers.
• Previous research indicated TP53 SNP215 variant impacts CML risk and outcome.

Purpose of the Study:

• To investigate the role of MDM2 genetic variants in CML susceptibility.
• To evaluate the association of MDM2 variants with treatment response to TKIs in CML patients.

Main Methods:

• Genotyping of five MDM2 promoter variants (del1518, SNP309, SNP285, SNP288, SNP344) in 135 CML patients and 136 healthy controls.
• Analysis of genotype-phenotype correlations with CML susceptibility and TKI treatment response.
• Combinatorial analysis of MDM2 variants with TP53 SNP215.

Main Results:

• MDM2 variants did not influence CML susceptibility.
• Individuals with MDM2 SNP309 G/G genotypes showed increased risk of molecular response failure to TKIs (p=0.044).
• Specific MDM2 genotypes (del1518 del allele, del1518-SNP309 combinations) were associated with improved overall survival in non-responders.
• Combined alternative MDM2 SNP309 and TP53 SNP215 genotypes correlated with faster achievement of molecular response (MR2, MMR) in non-responders.

Conclusions:

• MDM2 genetic variants do not affect CML susceptibility.
• Specific MDM2 genotypes significantly influence clinical outcomes and TKI treatment response in CML.
• Combinations of MDM2 and TP53 genotypes may predict favorable treatment responses, highlighting their role as potential prognostic biomarkers.