Glucocorticoid-receptor-gene defects and resistance to glucocorticoid-induced apoptosis in human leukemic cell lines

International Journal of Cancer. Journal International Du Cancer
M HalaR Kofler

Abstract

The application of glucocorticoids (GC3) in human leukemia is based on apoptosis induction but is often hampered by GC resistance. To delineate resistance mechanisms, we examined 5 GC-resistant leukemic cell lines, termed CEM-C7.R1-R5, isolated from the GC-sensitive human acute-T-cell-leukemic line, CCRF-CEM-C7, by selection in GC-containing medium. GC resistance was ascertained by analyzing cell-cycle progression, proliferation, and apoptosis. Radioreceptor assays revealed absence of ligand-binding activity in all clones, suggesting that defects in GC-receptor(GR) expression cause GC resistance. Analyses of the GR gene revealed that all but one (CEM-C7.R5) of the clones were heterozygous for the previously described L753F mutation. CEM-C7.R5 was either hemi- or homozygous for the L753F mutation and, hence, lacked a functional GR. Sequencing of the allele not carrying the L753F mutation of the other GC-resistant sub-lines revealed additional mutations in the GR gene in 3 cases: CEM-C7.R1 and R2 had a base-pair deletion in exon 9 (deltaT740) that resulted in a reading-frame shift and a pre-terminal in-frame stop. Translation of this mutant mRNA would produce a protein lacking 32 amino acids and expressing 4 altered residues at i...Continue Reading

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Citations

Dec 11, 2008·Journal of the National Cancer Institute·Nicolas PottierMeyling H Cheok
May 24, 2011·The Journal of Endocrinology·George SchlossmacherAnne White
Sep 13, 2011·Veterinary Immunology and Immunopathology·Akira MatsudaHiroshi Matsuda
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Sep 10, 2014·Proceedings of the National Academy of Sciences of the United States of America·Francis RobertJerry Pelletier
Nov 2, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Stefan SchmidtReinhard Kofler
Jul 12, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sang-Woo KimRicardo C T Aguiar
Dec 19, 2006·Molecular Cancer Therapeutics·Beatriz Sánchez-VegaVarsha Gandhi
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