Differential epigenetic regulation between the alternative promoters, PRDM1 alpha and PRDM1 beta, of the tumour suppressor gene PRDM1 in human multiple myeloma cells

Abstract

Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow. The transcription factor PRDM1 is a master regulator of plasma cell development and is considered to be an oncosuppressor in several lymphoid neoplasms. The PRDM1 beta isoform is an alternative promoter of the PRDM1 gene that may interfere with the normal role of the PRDM1 alpha isoform. To explain the induction of the PRDM1 beta isoform in MM and to offer potential therapeutic strategies to modulate its expression, we characterized the cis regulatory elements and epigenetic status of its promoter. We observed unexpected patterns of hypermethylation and hypomethylation at the PRDM1 alpha and PRDM1 beta promoters, respectively, and prominent H3K4me1 and H3K9me2 enrichment at the PRDM1 beta promoter in non-expressing cell lines compared to PRDM1 beta-expressing cell lines. After treatment with drugs that inhibit DNA methylation, we were able to modify the activity of the PRDM1 beta promoter but not that of the PRDM1 alpha promoter. Epigenetic drugs may offer the ability to control the expression of the PRDM1 alpha/PRDM1 beta promoters as components of novel therapeutic approaches.