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Dual Glutathione‐ S ‐Transferase‐θ1 and ‐μ1 Gene Deletions Determine Imatinib Failure in Chronic Myeloid Leukemia
Author(s) -
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
Publication year - 2014
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2014.176
Subject(s) - gstp1 , imatinib , myeloid leukemia , glutathione s transferase , medicine , single nucleotide polymorphism , gene , chronic myelogenous leukemia , oncology , pharmacology , cancer research , leukemia , biology , genetics , genotype , glutathione , biochemistry , enzyme
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. Clinical Pharmacology & Therapeutics (2014); 96 6, 694–703. doi: 10.1038/clpt.2014.176