A Single Nucleotide Polymorphism in the Coding Sequence of BIM Is Associated with Poor Prognostic in Chronic Myeloid Leukaemia Treated by Imatinib

Abstract 1683

BIM is a pro-apoptotic protein essential to tyrosine kinase inhibitors (TKI) response in chronic myeloid leukaemia (CML) patients. Thus, mutations in BIM sequence could lead to imatinib resistance independently of BCR-ABL mutations. Recently, a deletion polymorphism in intron 2 of BIM was demonstrated to confer intrinsic TKI resistance in asiatic patients (Ng et al, nature medicine, 2012). However the Caucasian population is not concerned by this intronic deletion polymorphism. So, in the current study we performed BIM coding sequence analysis in 72 CML imatinib-treated patients and among them 40 were resistant to imatinib in our center from French population of patients. For twenty patients, the disease evolved in either acceleration or blastic phases at least once during the study. We did not find any mutation with amino-acid change in the BIM coding sequence. However, we observed a silent single nucleotide polymorphism (SNP) c465C>T (rs724710) in the region coding for the active BH3 domain. A strong statistic link was found between the presence of the T allele of this polymorphism and the Sokal high risk group (p=0.0065). The frequency of the T allele was found higher in non responsive patients than in a local healthy donor reference population (p=0.0049). Similarly, the analysis showed an association of this T allele with the frequency of mutations on the tyrosine kinase domain of BCR-ABL (p<0.001) but not with additional chromosomal alterations. Moreover, the presence of the allele T significantly lengthened the time of achievement of major molecular remission. Finally, the presence of the T allele was found related to a decreased basal expression of the Bim mRNA in the circulating mononuclear cells of healthy donors. These results suggest that analysis of the c465C>T SNP of BIM could be useful for predicting the outcome of CML patients under imatinib treatment.