Divergent mechanisms of glucocorticoid resistance in experimental models of pediatric acute lymphoblastic leukemia.
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.
Bachmann
Petra S
PS
Children's Cancer Institute Australia for Medical Research, The University of New South Wales, Sydney, Australia.
Gorman
Rosemary
R
Papa
Rachael A
RA
Bardell
Jane E
JE
Ford
Jette
J
Kees
Ursula R
UR
Marshall
Glenn M
GM
Lock
Richard B
RB
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002648:Child; D003907:Dexamethasone / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009930:Organic Chemicals / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D009930:Organic Chemicals; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; C474557:SU 11657; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D003907:Dexamethasone; D020794:Receptor Protein-Tyrosine Kinases