title: Dual glutathione-S-transferase-θ1 and -μ1 gene deletions determine imatinib failure in chronic myeloid leukemia.
abstract: Approximately 40% of patients with chronic myeloid leukemia (CML) receiving imatinib fail treatment. There is an increased risk of CML in subjects with (i) deletions of genes encoding glutathione-S-transferase (GST)-θ1 (GSTT1) and -μ1, (GSTM1) and (ii) the GST-π1 (GSTP1) single-nucleotide polymorphism (SNP) Ile105Val (GSTP1*B; rs1695); however, their effects on imatinib treatment outcome are not known. Here, we assess the role of these GSTs in relation to imatinib treatment outcome in 193 CML patients. Deletion of GSTT1 alone, or in combination with deletion of the GSTM1 gene, significantly increased the likelihood of imatinib failure (P = 0.021 and P < 0.001, respectively). The GSTP1*B SNP was not associated with time to imatinib failure. Losses of the GSTT1 and GSTM1 genes are therefore important determinants of imatinib failure in CML. Screening for GSTT1 and GSTM1 gene deletions during diagnosis may identify patients who may be better treated using an alternative therapy.
authors.affiliation: Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Davies
authors.affiliation: Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Giannoudis
authors.affiliation: The Wolfson Centre for Personalised Medicine, Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Zhang
authors.affiliation: Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: G
authors.initials: G
authors.lastname: Austin
authors.affiliation: Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: T L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Faculty of Medicine, University of Heidelberg, Mannheim, Germany.
authors.forename: M C
authors.initials: MC
authors.lastname: Müller
authors.affiliation: Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Foroni
authors.affiliation: Royal Free Hospital, London, UK.
authors.forename: P D
authors.initials: PD
authors.lastname: Kottaridis
authors.affiliation: The Wolfson Centre for Personalised Medicine, Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Clark
mesh_terms: D001549:Benzamides / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017353:Gene Deletion; D018628:Gene Dosage; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000502:physiology; D005982:Glutathione Transferase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D017211:Treatment Failure
chemical_list: D001549:Benzamides; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D000068877:Imatinib Mesylate; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C413545:glutathione S-transferase T1