Dual Glutathione‐S‐Transferase‐θ1 and ‐μ1 Gene Deletions Determine Imatinib Failure in Chronic Myeloid Leukemia. Issue 6 (4th September 2014)

• Record Type: Journal Article
• Authors: Davies, A; Giannoudis, A; Zhang, J E; Austin, G; Wang, L; Holyoake, T L; Müller, M C; Foroni, L; Kottaridis, P D; Pirmohamed, M; Clark, R E
• Is Part Of: Clinical pharmacology & therapeutics. Volume 96:Issue 6(2014)
• Page Start: 694
• Page End: 703
• Publication Date: 2014-09-04
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1038/clpt.2014.176
• Languages: English
• ISSNs: 0009-9236

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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‐<italic>S</italic>‐transferase (GST)‐θ1 (<italic>GSTT1</italic>) and ‐μ1, (<italic>GSTM1</italic>) and (ii) the GST‐π1 (<italic>GSTP1</italic>) single‐nucleotide polymorphism (SNP) Ile105Val (<italic>GSTP1</italic>*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 <italic>GSTT1</italic> alone, or in combination with deletion of the <italic>GSTM1</italic> gene, significantly increased the likelihood of imatinib failure (<italic>P</italic> = 0.021 and <italic>P</italic> < 0.001, respectively). The <italic>GSTP1*B</italic> SNP was not associated with time to imatinib failure. Losses of the <italic>GSTT1</italic> and <italic>GSTM1</italic> genes are therefore important determinants of imatinib failure in CML. Screening for <italic>GSTT1</italic> and <italic>GSTM1</italic> gene deletions during diagnosis may identify patients who may be better treated using an alternative therapy.</p> <p> <italic>Clinical Pharmacology & Therapeutics</italic> (2014); <bold>96</bold> 6, 694–703. doi:<ext-link ext-link-type="doi" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">10.1038/clpt.2014.176</ext-link></p> </abstract>