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

Int J Cancer. 1996 Nov 27;68(5):663-8. doi: 10.1002/(SICI)1097-0215(19961127)68:5<663::AID-IJC17>3.0.CO;2-2.


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 its new C terminus. CEM-C7.R3 harbored a non-sense mutation (Q710X) in exon 8, and its mRNA would be translated into a protein lacking 67 residues. Only CEM-C7.R4 cells were devoid of mutations in the coding region of the L753F negative allele. These data suggest that, in the CCRF-CEM acute-lymphatic-leukemia model, mutations in the GR-gene coding region represent one, but not the only, cause of GC resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Apoptosis / drug effects*
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic
  • Glucocorticoids / administration & dosage*
  • Humans
  • Leukemia / genetics*
  • Leukemia / pathology
  • Molecular Sequence Data
  • Mutation
  • Receptors, Glucocorticoid / genetics*
  • Tumor Cells, Cultured


  • Glucocorticoids
  • Receptors, Glucocorticoid