Differential Response Of Leukemic Blasts To Dexamethasone and Prednisone Occurs At Sub-Saturating Doses

Dexamethasone (dex) and prednisone (pred) are highly related glucocorticoids that are used in the treatment of leukemias and lymphomas. Recently it was shown that dex produces better outcomes in children with high-risk B cell precursor acute lymphoblastic leukemia than pred. Although this result was consistent with the accepted potencies of the two drugs, the reason for this difference is not well understood. Glucocorticoids work primarily by binding and activating the glucocorticoid receptor, which, when bound, associates with genomic response elements to orchestrate gene expression programs. We hypothesized that dex regulates key genes that drive apoptosis in BCP-ALL more strongly. To test this we used microarrays to measure the differential expression of genes in response to saturating doses of dex and pred in three cell lines. Dex and pred induced very similar patterns of gene expression in each cell type, with an overlap of about 60%. Surprisingly, when we compared the 40% of genes that were regulated by dex or pred alone in each cell line, there were no commonly regulated genes among all cell lines. Further, for the 150 genes commonly regulated by both dex and pred in all three cell lines, there were no differences in the magnitude of response, suggested that the difference might lie at a lower, more functional doses. We tested this using RNA sequencing at five concentrations of both dex and pred in a primary patient sample. Consistent with their potency, the average regulated gene required eight times more pred than dex. Interestingly, when we performed unsupervised clustering of regulated genes by concentration, we found more modest differences in the concentration required for the onset of regulation, and that pred selectively suppressed expression of a block of genes at lower concentrations. These data suggest that rather than specific genes being regulated by dex, or simply a more potent response of the same genes, that the difference in apoptosis induction may be due to surprisingly different responses at sub-saturating concentrations.