title: The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia.
abstract: Although the prognosis of chronic myeloid leukemia (CML) patients treated with imatinib is good, many fail to develop an optimal response or lose one. This heterogeneity could be attributed to the presence of human organic cation transporter-1 (hOCT1) single nucleotide polymorphisms (SNPs). In the present study, we analyzed the effect of 23 hOCT1 SNPs on imatinib treatment outcome in newly diagnosed CML patients using MassARRAY sequencing and pyrosequencing. The only SNP associated with outcome was M420del (rs35191146), with patients with the M420del demonstrating an increased probability of imatinib treatment failure. In CML cell lines transfected with M420del and/or M408V, M420del significantly decreased imatinib uptake, but this effect was countered if the M408V (rs628031) SNP was also present. A similar effect was seen for the uptake of the hOCT1 substrates TEA(+) and ASP(+). Finally, apparent hOCT1 mRNA levels were studied using both our earlier primers covering the M420del and another set that did not. Different mRNA expression was observed, explaining the disparity in published data on the prognostic importance of hOCT1 mRNA and highlighting the importance of avoiding common SNP sites in primer design. These data demonstrate that the common M420del SNP can modulate the outcome of imatinib treatment.
authors.affiliation: Section of Haematology, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Athina
authors.initials: A
authors.lastname: Giannoudis
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Jorgensen
authors.forename: George
authors.initials: G
authors.lastname: Xinarianos
authors.forename: Andrea
authors.initials: A
authors.lastname: Davies
authors.forename: Sudeep
authors.initials: S
authors.lastname: Pushpakom
authors.forename: Triantafilos
authors.initials: T
authors.lastname: Liloglou
authors.forename: Jieying-Eunice
authors.initials: JE
authors.lastname: Zhang
authors.forename: Gemma
authors.initials: G
authors.lastname: Austin
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: Panagiotis D
authors.initials: PD
authors.lastname: Kottaridis
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clark
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D027702:Organic Cation Transporter 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate