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 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.

journal_name

Int J Cancer

authors

Hala M,Hartmann BL,Böck G,Geley S,Kofler R

doi

10.1002/(SICI)1097-0215(19961127)68:5<663::AID-IJC

subject

Has Abstract

pub_date

1996-11-27 00:00:00

pages

663-8

issue

5

eissn

0020-7136

issn

1097-0215

pii

10.1002/(SICI)1097-0215(19961127)68:5<663::AID-IJC

journal_volume

68

pub_type

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