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Expression in Hematological Malignancies of a Glucocorticoid Receptor Splice Variant That Augments Glucocorticoid Receptor-mediated Effects in Transfected Cells¹

Departments of Internal Medicine [P. d. L., J. W. K., F. H. d. J., S. W. J. L.], Hematology [C. M. S., E. W., P. S.], and Endocrinology and Reproduction [A. O. B.], Erasmus University Rotterdam and University Hospital, Rotterdam, the Netherlands, and Endocrine Sciences Research Group, Faculty of Medicine, and School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom [A. W., I. J. B.]

Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor , the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor ß, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor , and glucocorticoid receptor P, of which the effects are unknown. In this study, 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 hematological tumors. Although the glucocorticoid receptor ß 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 present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor . These results suggest that the relative levels of the glucocorticoid receptor and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.

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