Abstract
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 IC(50) >10 micromol/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.
Highlights
Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, including childhood acute lymphoblastic leukemia (ALL; ref. 1) due to their ability to induce apoptosis of lymphoid cells [2]
We have previously shown that the in vivo and in vitro dexamethasone responses of a panel of childhood ALL biopsies established as xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice reflected the clinical outcome of the patients from whom the xenografts were derived [9, 22]
We have previously shown nuclear translocation of the glucocorticoid receptor (GR) following exposure of 11 continuous xenografts to dexamethasone for 5 h [9], and Fig. 3A and B extend these findings to confirm no notable differences in the kinetics of ligand-induced GR nuclear translocation between two sensitive (ALL-3 and ALL-16) and two resistant (ALL-7 and ALL-19) xenografts
Summary
Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, including childhood acute lymphoblastic leukemia (ALL; ref. 1) due to their ability to induce apoptosis of lymphoid cells [2]. 1) due to their ability to induce apoptosis of lymphoid cells [2]. The glucocorticoid-induced apoptotic response is mediated through the glucocorticoid receptor (GR), a member of the nuclear receptor family of ligand-dependent transcription factors, which is localized in the cytoplasm of unstimulated cells [3]. Ligand binding to the GR results in its dissociation from chaperone proteins that tether the receptor in the cytoplasm, causing a conformational change in the protein that unmasks domains for nuclear translocation, receptor dimerization, DNA binding, and transactivation [2]. Changes in gene expression result in proteolytic activation of caspases that cleave critical cellular substrates and are responsible for the hallmark changes associated with apoptosis [4]
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