Glucocorticoid receptors and resistance to glucocorticoids in hematologic malignancies

Glucocorticoids are highly effective in inducing the cytolysis of cells of lymphocytic origin. This property has resulted in their incorporation into chemotherapy regimens used in the treatment of hematologic malignancies. Studies at the molecular and cellular levels have demonstrated that the hormone-induced cytolytic response is mediated through a highly specific cytoplasmic glucocorticoid receptor (GR). The GR has been cloned and sequenced and found to be organized into a discrete series of domains which mediate the receptor functions of hormone binding, nuclear translocation, DNA binding and transcriptional modulation. Thus, the binding of glucocorticoids by the GR induces a series of cellular events which result in the activation or repression of a network of glucocorticoid responsive genes and produces a specific cellular response. Prolonged exposure to glucocorticoids ultimately causes resistance to develop; thereby limiting the usefulness of this class of drugs. Studies addressing the mechanism of resistance have shown that the GR is the primary target of genetic alterations that lead to resistance to cytolysis. Using mouse and human cell lines as model systems, it has been shown that the vast majority of glucocorticoid resistant mutants express low levels or altered forms of the GR. Similarly, in vivo studies on patients have suggested that low GR levels are associated with a poor response to glucocorticoid based therapies. Recently, aberrant GR isolated from a patient with multiple myeloma resistant to glucocorticoids were found to harbor deletions in their hormone binding domains. Sequencing of the receptors suggested that each arose as a result of alternate splicing events. In both cases, the latter event produces a receptor unable to bind hormone leading to the speculation that alternate splicing may serve as a mechanism by which a cell evades the effects of glucocorticoids. The therapeutic implications for patients expressing aberrant receptors is discussed.