title: A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia.
abstract: 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.affiliation: Department of Haematology, Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Jacob
authors.initials: J
authors.lastname: Grinfeld
authors.forename: Gareth
authors.initials: G
authors.lastname: Gerrard
authors.forename: Mary
authors.initials: M
authors.lastname: Alikian
authors.forename: Juan
authors.initials: J
authors.lastname: Alonso-Dominguez
authors.forename: Sakuntala
authors.initials: S
authors.lastname: Ale
authors.forename: Mikel
authors.initials: M
authors.lastname: Valgañon
authors.forename: Georgios
authors.initials: G
authors.lastname: Nteliopoulos
authors.forename: Deborah
authors.initials: D
authors.lastname: White
authors.forename: David
authors.initials: D
authors.lastname: Marin
authors.forename: Corinne
authors.initials: C
authors.lastname: Hedgley
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Brien
authors.forename: Richard
authors.initials: R
authors.lastname: Clark
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: Dragana
authors.initials: D
authors.lastname: Milojkovic
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D001692:Biological Transport; D018389:Codon, Nonsense; D004351:Drug Resistance / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000097:blood; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D001549:Benzamides; D018389:Codon, Nonsense; D027702:Organic Cation Transporter 1; D010879:Piperazines; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: chronic myeloid leukaemia; drug resistance; prognostic factors; tyrosine kinases