EHA 2016
Mutations associated with imatinib response in CML
Katerina Machova Polakova - Institute of Hematology and Blood Transfusion, Prague, Czech Republic
At the conference we are going to present our very recent work on pharmacogenomics which is the study of the inherited basis of individual differences in drug response. So the pharmacogenomic study in our lab was focussed on finding some genetic basis of our CML patients that may be associated with imatinib response. In this work we were looking in CML patients who were treated with imatinib first line with the standard dose of imatinib. It means that the dose was not changed during the follow-up which was the first twelve months since imatinib initiation because the twelve month mark was the criteria for response evaluations. We looked at the single nucleotide polymorphisms in the sequences of promotors of genes that encode drug transportations through the plasmatic membrane and we selected nineteen genes and we performed high throughput single nucleotide polymorphism screening in the promotor sequences of those nineteen genes encoding drug transporters. So among them I suppose five of the transporters have annotated function of imatinib transportation.
From the abstract I saw that the SLC and ABC genes were especially included. Can you tell us more about those as their role in healthy cells and how that changes in CML?
We see clearly from our results significant differences in the frequency of allele of identified SNPs in promotors of SLC22A4 and SLC22A5 between optimally responding patients to imatinib and non-optimally responding patients to imatinib. Comparing the allele frequency of those SNPs, identified SNPs, to a European population, SNPs frequency, comparison between optimally responding patients, non-optimally responding patients, with a European population we clearly saw the shift in allele frequencies in non-optimally responding patients in comparison to a European population.
We believe that those SNPs may be candidates to be implemented in real clinical practice but before that we need to prove this on a really large cohort of CML patients because for such association studies it’s really good to start with a cohort of, let’s say, 500 individuals which is always complicated when we’re working with a rare disease like chronic myeloid leukaemia is. So we believe we will have a nicely international collaboration on that to prove our observation on a really large cohort of CML patients before we may implement these SNPs into real clinical practice. But in our genetic analysis we perform linkage disequilibrium analysis with the identified SNPs and we found that those SNPs are in highly significant linkage disequilibrium with other regulatory single nucleotide polymorphisms which are located in non-coding intronic regions of both genes which assume that our findings may have a regulative basis and that the set of genotypes which is inherited for each patient may really matter or may result on what will be the expression of both genes and this may impact the expression of the protein, the carriers, imatinib carriers, and finally this may result on bio-availability of imatinib. We know that concentration of imatinib may cause resistance development in leukemic cells.
