| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Molecular Biology, Pathobiology and Genetics |
1 Northern Institute for Cancer Research and 2 Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
Requests for reprints: Julie A.E. Irving, Northern Institute for Cancer Research, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, United Kingdom. Phone: 44-191-246-4369; E-mail: j.a.e.irving{at}ncl.ac.uk.
Glucocorticoids are pivotal in the treatment of children with acute lymphoblastic leukemia (ALL) and have significant antileukemic effects in the majority of children. However, clinical resistance is a significant problem. Although cell line models implicate somatic mutations and loss of heterozygosity (LOH) of the glucocorticoid receptor (GR) gene as a mechanism of in vitro glucocorticoid resistance, the relevance of this mechanism as a cause of clinical resistance in children with ALL is not known. Mutational screening of all coding exons of the GR gene and LOH analyses were done in a large cohort of relapsed ALL. We show that somatic mutations and LOH of the GR rarely contribute to relapsed disease in children with ALL. However, we report the second case of ALL with a somatic mutation of the GR involving a 29-bp deletion in exon 8 and resulting in a truncated protein with loss of part of the ligand-binding domain. There was no evidence of a remaining wild-type allele. Allele-specific PCR detected the mutated clone at day 28 after presentation, which persisted at a low level throughout the disease course before relapse several years later. We hypothesize that the mutated allele present in a leukemic subclone at initial diagnosis was selected for during remission induction with glucocorticoids and contributed to the emergence of a glucocorticoid-resistant cell population.
This article has been cited by other articles:
|
|
 |
|
  J. Zhang, R. Ge, C. Matte-Martone, J. Goodwin, W. D. Shlomchik, M. J. Mamula, A. Kooshkabadi, M. P. Hardy, and D. Geller Characterization of a Novel Gain of Function Glucocorticoid Receptor Knock-in Mouse J. Biol. Chem., March 6, 2009; 284(10): 6249 - 6259. [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]
|
|
|
|
 |
|
 J. A. Meyers, J. Taverna, J. Chaves, A. Makkinje, and A. Lerner Phosphodiesterase 4 Inhibitors Augment Levels of Glucocorticoid Receptor in B Cell Chronic Lymphocytic Leukemia but Not in Normal Circulating Hematopoietic Cells Clin. Cancer Res., August 15, 2007; 13(16): 4920 - 4927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Bachmann, R. Gorman, R. A. Papa, J. E. Bardell, J. Ford, U. R. Kees, G. M. Marshall, and R. B. Lock Divergent Mechanisms of Glucocorticoid Resistance in Experimental Models of Pediatric Acute Lymphoblastic Leukemia Cancer Res., May 1, 2007; 67(9): 4482 - 4490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Schmidt, J. A. E. Irving, L. Minto, E. Matheson, L. Nicholson, A. Ploner, W. Parson, A. Kofler, M. Amort, M. Erdel, et al. Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor FASEB J, December 1, 2006; 20(14): 2600 - 2602. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
