Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells

Glucocorticoids play an important role in the treatment of a number of hema tological malignancies, such as multiple myeloma, The effects of glucocorti coids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid re ceptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have b een described,ed: glucocorticoid receptor beta, which reportedly has a domi nant negative effect on the actions of the glucocorticoid receptor alpha, a nd glucocorticoid receptor P, of which the effects are unknown. In this stu dy, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hemat ological tumor's, Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was pres ent in most hematological malignancies. In transient transfection studies i n several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha The se results suggest that the relative levels of the glucocorticoid receptor a and the glucocorticoid receptor P may play a role in the occurrence of gl ucocorticoid resistance in tumor cells during the treatment of hematologica l malignancies with glucocorticoids.