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