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Lookup NU author(s): Dr Pamela Kearns,
Dr Andrew Hall,
Professor Andrew Pearson
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Expression of three major classes of glutathione S-transferases (GSTs), i.e. alpha, mu and pi class, P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) were studied in childhood acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and normal peripheral blood lymphocytes by flow cytometry. In vitro cytotoxicity of 4-hydroxy-ifosfamide (IFOS), daunorubicin (DNR) and prednisolone (PRED) was assessed by the MTT assay. Expression of alpha, mu and pi class GST did not significantly differ between leukaemic cells from 100 initial and 14 unrelated relapse ALL patients (GST alpha P = 0.26; GST mu P = 0.09; GST pi P = 0.13). The expression of GST alpha (1.4-fold, P = 0.0004), GST pi (1.3-fold, P = 0.001) and to a lesser extent also GST mu (1.1-fold, P = 0.03) was higher in ALL compared with normal peripheral blood lymphocytes. Expression of GST mu and GST pi was significantly higher in 18 AML compared with 100 ALL patients at initial diagnosis (respectively 1.3-fold, P = 0.0005 and 2-fold, P < 0.0001). In contrast, GST alpha was median 2-fold lower expressed in the AML samples (P < 0.0001). Expression levels of alpha, mu and pi class GSTs were not related to the degree of resistance to IFOS, DNR and PRED nor to immunophenotype, white blood cell count or age at presentation of childhood ALL. One exception was a remarkably low expression of GST alpha in IFOS-sensitive samples compared with a heterogenous expression in IFOS-resistant samples (P = 0.02). Expression of GST pi, but not of GST alpha or GST mu, weakly correlated with the expression of MRP (Rs 0.36, P = 0.002, n = 74) but not with P-gp. However, a high expression of both GST pi and MRP was not associated with in vitro resistance to IFOS, DNR or PRED. The present data suggest that expression of GST pi is not linked to the degree of resistance to IFOS, DNR and PRED or clinical risk factors in childhood ALL. Whether the high expression of GST mu and GST pi in AML cells contributes to the relative resistance to IFOS, DNR and PRED compared with ALL samples (P less than or equal to 0.0001) warrants further study.
Author(s): Den Boer ML, Pieters R, Kazemier KM, Janka-Schaub GE, Henze G, Creutzig U, Kaspers GJL, Kearns PR, Hall AG, Pearson ADJ, Veerman AJP
Publication type: Article
Publication status: Published
Journal: British Journal of Haematology
ISSN (print): 0007-1048
ISSN (electronic): 1365-2141
PubMed id: 10050715
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