Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

Monika Jaruskova,Vladimir Benes,Katerina Machova Polakova,Vaclava Polivkova,Rajna Hercog,Pavla Pecherkova,Petra Belohlavkova,Nikola Curik,Eliska Motlova,Hana Klamova,Filip Vrbacky

doi:10.1186/s13046-017-0523-3

Abstract

BackgroundThrough high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia.MethodsIn silico analysis using publicly available databases was done to select the SLC and ABC genes and their promoters for the next-generation sequencing. SNPs associated with the imatinib response were identified using Fisher’s exact probability tests and subjected to the linkage disequilibrium analyses with regulatory loci of concerned genes. We analyzed cumulative achievement of major molecular response and probability of event free survival in relation to identified SNP genotypes in 129 CML patients and performed multivariate analysis for determination of genotypes as independent predictors of outcome. Gene expression analysis of eight cell lines naturally carrying different genotypes was performed to outline an impact of genotypes on the gene expression.ResultsWe observed significant differences in the frequencies of the rs460089-GC and rs460089-GG (SLC22A4) genotypes among rs2631365-TC (SLC22A5) genotype carriers that were associated with optimal and non-optimal responses, respectively. Loci rs460089 and rs2631365 were in highly significant linkage disequilibrium with 12 regulatory loci in introns of SLC22A4 and SLC22A5 encoding imatinib transporters. Genotype association analysis with the response to imatinib indicated that rs460089-GC carriers had a significantly higher probability of achieving a stable major molecular response (BCR-ABL1 transcript level below or equal to 0.1% in the international scale). In contrast, the rs460089-GG represented a risk factor for imatinib failure, which was significantly higher in rs460089-GG_rs2631365-TC carriers.ConclusionsThis exploratory study depicted potentially important genetic markers predicting outcome of imatinib treatment, which may be helpful for tailoring therapy in clinical practice.

Highlights

Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify Single nucleotide polymorphisms (SNPs) associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia
In silico analysis of the Solute carrier (SLC) and ATP binding cassette (ABC) genes Analysis using the National Center for Biotechnology Information (NCBI), UCSF PMT and Eukaryotic Promoter Database (EPD) databases demonstrated that the SLC and ABC gene groups are highly diverse and that their individual genes are scattered throughout the genome
For SNP screening in the promoter regions by next-generation sequencing (NGS), we selected 19 transporter-encoding genes with annotated drug transportation functions that were expressed in the liver, small intestine, bone marrow and leukocytes (Additional file 2: Table S2)

Summary

Introduction

Through high-throughput next-generation sequencing of promoters of solute carrier and ATP-binding cassette genes, which encode drug transporters, we aimed to identify SNPs associated with the response to imatinib administered for first-line treatment of patients with chronic myeloid leukemia. Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome (Ph) and fusion oncogene BCR-ABL1 and is currently very treatable with tyrosine kinase inhibitors (TKIs) that inhibit the tyrosine kinase activity of the chimeric BCR-ABL1 protein. The reduced bioavailability of imatinib in leukemic cells is an important pharmacokinetic factor that contributes to resistance development. Solute carrier (SLC) proteins facilitate drug entry into cells, whereas ATP binding cassette (ABC) transporters facilitate drug excretion. The best-studied multidrug efflux transporter in CML is ABCB1, which is overexpressed in blast crisis and contributes to the reduced effectiveness of chemotherapy in advanced disease [6, 7]

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