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A common novel splice variant of SLC 22 A 1 ( OCT 1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia
Author(s) -
Grinfeld Jacob,
Gerrard Gareth,
Alikian Mary,
AlonsoDominguez 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
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12591
Subject(s) - exon , single nucleotide polymorphism , imatinib , allele , snp , genotype , biology , medicine , genetics , microbiology and biotechnology , gene , myeloid leukemia
Summary 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 ( SLC 22 A 1, also termed OCT 1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed SLC22A1 m RNA levels and single nucleotide polymorphisms ( SNP s) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of SLC22A1 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 + allele) at the 3′ end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M 420del was found in 33% of patients and never in cis with 8 + (the 3 − allele). Significantly longer times to 1% and 0·1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8 + 8 + or 8 + N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8 + and 3 − (NN, 18%) showed the best outcomes overall. Thus, while SLC 22 A 1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so.