Abstract
Although glucocorticoids play an important role in the treatment of multiple myeloma, some patients do not respond or develop resistance. The glucocorticoid receptor (GR), a single gene, mediates the effects of glucocorticoids. Using a model system of a multiple myeloma cell line sensitive to glucocorticoids and its early and late resistant variants, we have analyzed mutations in the GR gene, detected the presence of different transcriptional isoforms, quantified their levels of expression, and identified the promoters that regulate their expression. Levels of GR transcripts were comparable with the expression of total GR protein. Development of resistance correlates with an overall reduction in GR mRNA levels. This decrease in GR levels is neither due to mutation of the gene nor due to methylation. GRalpha is the predominant isoform in the sensitive cell line decreasing in expression in the early resistant cells and virtually undetectable in late resistant cells. GR-P is expressed at equivalent levels in both sensitive and early resistant cells, whereas in the late resistant cells, GR-P is the predominant isoform. GR-A is only expressed in the early resistant cell line. GRbeta is the least expressed isoform in all cell lines. Interestingly, the level of expression of exon 1-exon 2 RNA fragments remains similar in sensitive and resistant cell lines. Resistant cells became sensitive to glucocorticoids after GRalpha transfection. In conclusion, we show different patterns of expression of the GR isoforms and provide evidence that a decline in the expression of GRalpha may be associated with development of resistance.
Highlights
Multiple myeloma is a relatively rare clonal B-cell malignancy characterized by the accumulation of terminally differentiated, antibody-producing plasma cells in the bone marrow
Our studies show different patterns of expression of the various glucocorticoid receptor (GR) isoforms between a glucocorticoid-sensitive cell line and its early and late resistant counterparts
To obtain independent verification of the steady-state RNA levels changes seen in array analysis, quantitative PCR analysis was done focusing on the GR gene, which shows the highest difference of expression between the cell lines
Summary
Multiple myeloma is a relatively rare clonal B-cell malignancy characterized by the accumulation of terminally differentiated, antibody-producing plasma cells in the bone marrow. Glucocorticoids are lipophilic compounds derived from cholesterol that have a wide range of biological activities. In addition to their physiologic roles, glucocorticoids induce apoptosis and cell cycle arrest in lymphoid cells, playing an important role in the treatment of multiple myeloma [1]. Multiple myeloma is a disease that is generally considered responsive to glucocorticoids, some patients do not respond and those that do respond eventually develop resistance to this therapy [4]. Studies in patients with leukemia have suggested that low GR protein levels are associated with a poor response to glucocorticoid treatment and to a mechanism of acquiring steroid resistance (9 – 11)
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