Document Detail


A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia.
MedLine Citation:
PMID:  24117365     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 SLC22A1 mRNA levels and single nucleotide polymorphisms (SNPs) 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. M420del 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 SLC22A1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so.
Authors:
Jacob Grinfeld; Gareth Gerrard; Mary Alikian; Juan Alonso-Dominguez; Sakuntala Ale; Mikel Valgañon; Georgios Nteliopoulos; Deborah White; David Marin; Corinne Hedgley; Stephen O'Brien; Richard Clark; John M Goldman; Dragana Milojkovic; Jane F Apperley; Letizia Foroni
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-10-10
Journal Detail:
Title:  British journal of haematology     Volume:  -     ISSN:  1365-2141     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-10-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 John Wiley & Sons Ltd.
Affiliation:
Department of Haematology, Imperial College Healthcare NHS Trust, London, UK.
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