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Divergent Mechanisms of Glucocorticoid Resistance in Experimental Models of Pediatric Acute Lymphoblastic Leukemia

¹ Children's Cancer Institute Australia for Medical Research, ² The University of New South Wales, and ³ The Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Sydney, Australia; and ⁴ The Telethon Institute for Child Health Research, and Centre for Child Health Research, The University of Western Australia, Perth, Australia

Requests for reprints: Richard Lock, Children's Cancer Institute Australia, P.O. Box 81, High Street, Randwick, NSW 2031, Australia. Phone: 61-2-9382-1846; Fax: 61-2-9382-1850; E-mail: rlock{at}ccia.unsw.edu.au.

Cell line models of glucocorticoid resistance in childhood acute lymphoblastic leukemia (ALL) almost invariably exhibit altered glucocorticoid receptor (GR) function. However, these findings are incongruous with those using specimens derived directly from leukemia patients, in which GR alterations are rarely found. Consequently, mechanisms of glucocorticoid resistance in the clinical setting remain largely unresolved. We present a novel paradigm of glucocorticoid resistance in childhood ALL, in which patient biopsies have been directly established as continuous xenografts in immune-deficient mice, without prior in vitro culture. We show that the GRs from six highly dexamethasone-resistant xenografts (in vitro IC₅₀ >10 µmol/L) exhibit no defects in ligand-induced nuclear translocation and binding to a consensus glucocorticoid response element (GRE). This finding contrasts with five commonly used leukemia cell lines, all of which exhibited defective GRE binding. Moreover, whereas the GRs of dexamethasone-resistant xenografts were transcriptionally active, as assessed by the ability to induce the glucocorticoid-induced leucine zipper (GILZ) gene, resistance was associated with failure to induce the bim gene, which encodes a proapoptotic BH3-only protein. Furthermore, the receptor tyrosine kinase inhibitor, SU11657, completely reversed dexamethasone resistance in a xenograft expressing functional GR, indicating that pharmacologic reversal of glucocorticoid resistance in childhood ALL is achievable. [Cancer Res 2007;67(9):4482–90]

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