Pharmacogenetic study of p53 gene signaling pathway in chronic myeloid leukemia.

MARTÍNEZ LAHITOU IM; MOIRAGHI B; FONTECHA MB; WEICH N; LARRIPA IB; ANADÓN MR; BENGIÓ R; FUNDIA AF

CABA

Simposio; Frontiers in Biosciencie 3; 2018

Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA, CONICET ? Partner Institute of the Max Planck Society)

Chronic myeloid leukemia (CML), characterized by the BCR-ABL1 fusion oncogene, is successfully treated by tyrosine kinase inhibitors (TKIs). However, many patients receiving TKIs develop resistance or fail therapy and pharmacogenetics may play an important role in the final clinical outcome. We have recently shown that the Single Nucleotide Polymorphism (SNP) 213G>C on p53 gene is associated with worse treatment response in patients with CML. The aim of this work was to perform a deep pharmacogenetic study of gene polymorphisms in the p53 signaling pathway in CML by investigating regulators of p53 activity as MDM2 and NQO1 and less common variants on p53 gene. Genomic DNAs of 137 treated patients were evaluated. Five polymorphisms: MDM2 indel1518, MDM2 309T>G, NQO1 609C>T and two intronic variants of p53 (IVS3 16 bp indel and IVS6+62A>G) were genotyped by different PCR methods and direct sequencing. Treatment response was defined according the European LeukemiaNet. TKIs failure was detected in 64 patients, 20 of them exhibited BCR-ABL1 mutations. Individual analysis of genotype and allele frequencies of each polymorphism showed no association with the clinico-pathological data: age, gender, disease phase, Sokal score, cytogenetic/molecular responses, BCR-ABL1 levels and ABL1 mutations. To measure the potential joint effect of the studied polymorphisms, the comparison of combined genotypes stratified according to the different clinic-pathological characteristics was performed. An increased risk of major cytogenetic response failure was found for patients carrying MDM2 ins/ins and 309G/G genotypes (p=0.030; OR=7.22; CI: 1.17-36.90). This study shows for the first time that both MDM2 polymorphisms jointly influence on the cytogenetic response. Possibly, both MDM2 polymorphisms inhibit p53 expression which in turn impairs the TKIs induced-apoptosis being responsible of the treatment failure. Moreover, analysis of MDM2 variation may facilitate the identification of patients at high risk of poor disease outcome.