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	Petra S Bachmann, Rosemary Gorman, Karen L Mackenzie, Louise Lutze-Mann, Richard B Lock
Journal	Blood (Blood) Vol. 105 Issue 6 Pg. 2519-26 (Mar 15 2005) ISSN: 0006-4971 [Print] United States
PMID	15572593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents, Hormonal Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Ligands Membrane Proteins Proto-Oncogene Proteins Receptors, Glucocorticoid Dexamethasone
Topics	Active Transport, Cell Nucleus Adolescent Animals Antineoplastic Agents, Hormonal (administration & dosage, metabolism) Apoptosis Apoptosis Regulatory Proteins (metabolism) Bcl-2-Like Protein 11 Burkitt Lymphoma (drug therapy, metabolism) Cell Nucleus (metabolism) Child Child, Preschool Dexamethasone (administration & dosage, metabolism) Drug Resistance, Neoplasm Female Gene Expression Regulation, Leukemic Humans Ligands Male Membrane Proteins (metabolism) Mice Mice, Inbred NOD Mice, SCID Neoplasm Transplantation Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, immunology, pathology) Proto-Oncogene Proteins (metabolism) Receptors, Glucocorticoid (metabolism) Signal Transduction Transplantation, Heterologous

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