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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2519-2526. Prepublished online as a Blood First Edition Paper on November 30, 2004; DOI 10.1182/blood-2004-05-2023. This Article Full Text (PDF) All Versions of this Article: 2004-05-2023v1 105/6/2519    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bachmann, P. S Articles by Lock, R. B Search for Related Content PubMed PubMed Citation Articles by Bachmann, P. S Articles by Lock, R. B Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 28, 2004 Accepted November 6, 2004 Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor Petra S Bachmann, Rosemary Gorman, Karen L MacKenzie, Louise Lutze-Mann, and Richard B Lock* Children's Cancer Institute Australia for Medical Research, Sydney, Australia; University of New South Wales, Sydney, Australia Children's Cancer Institute Australia for Medical Research, Sydney, Australia University of New South Wales, Sydney, Australia * Corresponding author; email: richard.lock{at}unsw.edu.au. 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. In spite of 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 pro-apoptotic 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. C. Jaramillo, J. B. Frye, J. D. Crapo, M. M. Briehl, and M. E. Tome Increased Manganese Superoxide Dismutase Expression or Treatment with Manganese Porphyrin Potentiates Dexamethasone-Induced Apoptosis in Lymphoma Cells Cancer Res., July 1, 2009; 69(13): 5450 - 5457. [Abstract] [Full Text] [PDF] C. V. Cox, P. Diamanti, R. S. Evely, P. R. Kearns, and A. Blair Expression of CD133 on leukemia-initiating cells in childhood ALL Blood, April 2, 2009; 113(14): 3287 - 3296. [Abstract] [Full Text] [PDF] N. Pottier, W. Yang, M. Assem, J. C. Panetta, D. Pei, S. W. Paugh, C. Cheng, M. L. Den Boer, M. V. Relling, R. Pieters, et al. The SWI/SNF Chromatin-Remodeling Complex and Glucocorticoid Resistance in Acute Lymphoblastic Leukemia J Natl Cancer Inst, December 17, 2008; 100(24): 1792 - 1803. [Abstract] [Full Text] [PDF] S. Sharma and A. Lichtenstein Dexamethasone-induced apoptotic mechanisms in myeloma cells investigated by analysis of mutant glucocorticoid receptors Blood, August 15, 2008; 112(4): 1338 - 1345. [Abstract] [Full Text] [PDF] G. Neale, X. Su, C. L. Morton, D. Phelps, R. Gorlick, R. B. Lock, C. P. Reynolds, J. M. Maris, H. S. Friedman, J. Dome, et al. Molecular Characterization of the Pediatric Preclinical Testing Panel Clin. Cancer Res., July 15, 2008; 14(14): 4572 - 4583. [Abstract] [Full Text] [PDF] C. L. Hann, V. C. Daniel, E. A. Sugar, I. Dobromilskaya, S. C. Murphy, L. Cope, X. Lin, J. S. Hierman, D. L. Wilburn, D. N. Watkins, et al. Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer Cancer Res., April 1, 2008; 68(7): 2321 - 2328. [Abstract] [Full Text] [PDF]

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