A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia. (10th October 2013)

• Record Type: Journal Article
• Authors: Grinfeld, Jacob; Gerrard, Gareth; Alikian, Mary; Alonso‐Dominguez, Juan; Ale, Sakuntala; Valgañon, Mikel; Nteliopoulos, Georgios; White, Deborah; Marin, David; Hedgley, Corinne; O'Brien, Stephen; Clark, Richard; Goldman, John M.; Milojkovic, Dragana; Apperley, Jane F.; Foroni, Letizia
• Is Part Of: British journal of haematology. Volume 163:Number 5(2013:Dec.)
• Page Start: 631
• Page End: 639
• Publication Date: 2013-10-10
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12591
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh12591-abs-0001"> <title>Summary</title> <p>Approximately one‐third of patients with chronic myeloid leukaemia will fail to achieve or maintain responses to imatinib. Changes in solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also termed OCT1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed <italic>SLC22A1</italic> mRNA levels and single nucleotide polymorphisms (SNPs) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of <italic>SLC22A1</italic> expression did not significantly correlate with imatinib failure or achievement of molecular remission. The SNP 408V>M (g.1222G>A) was present in 65% of patients and was associated in all cases with an eight base‐pair insertion (8<sup>+</sup> allele) at the 3′ end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M420del was found in 33% of patients and never in <italic>cis</italic> with 8<sup>+</sup> (the 3<sup>−</sup> allele). Significantly longer times to 1% and 0·1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8<sup>+</sup>8<sup>+</sup> or 8<sup>+</sup>N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8<sup>+</sup> and 3<sup>−</sup> (NN, 18%) showed the best outcomes overall. Thus, while <italic>SLC22A1</italic> expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so.</p> </abstract>