title: Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor.
abstract: Glucocorticoids are among the most effective agents used in the treatment of childhood acute lymphoblastic leukemia (ALL), and patient response to treatment is an important determinant of long-term outcome. Despite its clinical significance, the molecular basis of glucocorticoid resistance in lymphoid malignancies is still poorly understood. We have recently developed a highly clinically relevant experimental model of childhood ALL, in which primary childhood ALL biopsies were established as xenografts in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The in vivo and in vitro responses of a panel of these xenografts to the glucocorticoid, dexamethasone, reflected the outcome of the patients from whom they were derived. In this report we show that glucocorticoid resistance in B-cell precursor (BCP) ALL xenografts was not due to down-regulation of the glucocorticoid receptor (GR) nor to defective ligand binding of the GR. Moreover, dexamethasone-induced GR translocation from the cytoplasm to the nucleus was comparable in all xenografts. However, glucocorticoid resistance was associated with profoundly attenuated induction of the BH3-only proapoptotic protein, Bim, when xenograft cells were exposed to dexamethasone. These results show that dexamethasone resistance in BCP ALL xenografts occurs downstream of ligand-induced nuclear translocation of the GR, but upstream of Bim induction.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, PO Box 81, High Street, Randwick, NSW 2031, Australia.
authors.forename: Petra S
authors.initials: PS
authors.lastname: Bachmann
authors.forename: Rosemary
authors.initials: R
authors.lastname: Gorman
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mackenzie
authors.forename: Louise
authors.initials: L
authors.lastname: Lutze-Mann
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone