MiR-pharmacogenetics of methotrexate in childhood B-cell acute lymphoblastic leukemia.

Abstract

Methotrexate (MTX), the key drug in childhood B-cell acute lymphoblastic leukemia (B-ALL) therapy, often causes toxicity. An association between genetic variants in MTX transport genes and toxicity has been found. It is known that these transporters are regulated by microRNAs (miRNAs), and miRNA single nucleotide polymorphisms (SNPs) interfere with miRNA levels or function. With regard to B-cell ALL, we have previously found rs56103835 in miR-323b that targets ABCC4 associated with MTX plasma levels. Despite these evidences and that nowadays a large amount of new miRNAs have been annotated, studies of miRNA polymorphisms and MTX toxicity are almost absent. Therefore, the aim of this study was to determine whether there are other variants in miRNAs associated with MTX levels. Blood samples of 167 Spanish patients with pediatric B-cell ALL treated with the LAL-SHOP protocol were analyzed. We selected all the SNPs described in pre-miRNAs with a minor allele frequency more than 1% (213 SNPs in 206 miRNAs) that could regulate MTX transporters because the miRNAs that target MTX transporter genes are not completely defined. Genotyping was performed with VeraCode GoldenGate platform. Among the most significant results, we found rs56292801 in miR-5189, rs4909237 in miR-595, and rs78790512 in miR-6083 to be associated with MTX plasma levels. These miRNAs were predicted, in silico, to regulate genes involved in MTX uptake: SLC46A1, SLC19A1, and SLCO1A2. In this study, we detected three SNPs in miR-5189, miR-595, and miR-6083 that might affect SLC46A1, SLC19A1, and SLCO1A2 MTX transport gene regulation and could affect MTX levels in patients with pediatric B-cell ALL.