Imbalanced Expression of the Glucocorticoid Receptor Isoforms in Cultured Lymphocytes from a Patient with Systemic Glucocorticoid Resistance and Chronic Lymphocytic Leukemia

Abstract

The human glucocorticoid receptor (GR) is expressed as two alternatively spliced isoforms, GRα and GRβ. Whereas GRα is a hormone-activated transcription factor, GRβ does not bind glucocorticoids (GCs), is transcriptionally inactive, and is a potential inhibitor of activated GRα. 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 lymphocytic leukemia (CLL). We studied a patient with generalized GC resistance and CLL. GR number in the patient's transformed lymphocytes was approximately one half that of control cells with a ∼10-fold reduction in binding affinity for dexamethasone.In vitroapoptosis induction in CLL cells was delayed in response to GCs, but not to other apoptosis inducers. Sequencing of the GR cDNA and gene including the 2.3-kb coding region, the intron/exon junctions, the known 5′-regulatory region, and ∼300 bp of the 3′-region revealed no alterations. Western blot with an N-terminal antibody showed normal levels of immunoreactive GR, but quantitative analysis with isoform-specific C-terminal antibodies revealed a markedly reduced GRα expression, and high GRβ expression. These findings indicate that imbalanced expression of the GR isoforms may be a mechanism of GC resistance, and may have implications for tumorigenesis by enhancing cell survival.