Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia

The human glucocorticoid receptor (GR) is expressed as two alternatively sp liced isoforms, GR alpha and GR beta. Whereas GR alpha is a hormone-activat ed transcription factor, GR beta does not bind glucocorticoids (GCs), is tr anscriptionally inactive, and is a potential inhibitor of activated GR alph a, Differential expression of GR isoforms may play a role in generalized or tissue-specific GC resistance. GCs induce apoptosis in neoplastic lymphoid cells; and, defective apoptosis is implicated in the genesis of chronic ly mphocytic leukemia (CLL). We studied a patient with generalized GC resistan ce and CLL. GR number in the patient's transformed lymphocytes was approxim ately one half that of control cells with a similar to 10-fold reduction in binding affinity for dexamethasone. In vitro apoptosis induction in CLL ce lls was delayed in response to GCs, but not to other apoptosis inducers. Se quencing of the GR cDNA and gene including the 2.3-kb coding region, the in tron/exon junctions, the known 5'-regulatory region, and similar to 300 bp of the 3'-region revealed no alterations, Western blot with an N-terminal a ntibody showed normal levels of immunoreactive GR, but quantitative analysi s with isoform-specific C-terminal antibodies revealed a markedly reduced G R alpha expression, and high GR beta expression, These findings indicate th at imbalanced expression of the GR isoforms may be a mechanism of GC resist ance, and may have implications for tumorigenesis by enhancing cell surviva l, (C) 1999 Academic Press.