SMRT; Not So Smart in Multiple Myeloma.

Multiple myeloma (MM), a clonal B-cell malignancy, characterized by accumulation of plasma cells in bone marrow is the second most hematological malignancy in United States. In the BM, the myeloma and stromal cells secrete cytokines, which support the growth and survival of the myeloma cells. We previously showed that JAG2, one of the NOTCH ligand, is over-expressed in MM cells (Blood. 2004 Dec 1;104(12)). We hypothesized that over-expression of JAG2 in myeloma cells induce secretion of IL-6 from the stromal cells and subsequently enhances the proliferation of myeloma cells. JAG2 has been shown to be over-expressed in all cell lines and patient samples studied To identify the mechanism for JAG2 overexpression in MM cells, we assessed the potential modifications of the JAG2 promoter in MM cell lines as well as patient samples (an JAG2 negative controls) by studying both methylation and histone acetylation level of the JAG2 promoter. We show that difference in H4 acetylation level might play a crucial role in JAG2 expression. Acetylation state of histones can be regulated by the recruitment of histone deacetylases (HDACs). HDACs are typically recruited to promoter regions through interaction with nuclear co-repressors such as SMRT. The cell lines and patient samples studied presented significantly reduced levels of SMRT. Therefore, based on these observations we propose a model in which partial down-regulation of SMRT recruits less active HDAC3 (as confirmed by immunoprecipitation). As a result the deactylation process of histones in the JAG2 promoter region has been impaired and the cells lost their regulatory mechanism on transcriptional regulation of JAG2. This provides a mechanistic explanation for JAG2 over-expression in MM and on the direct involvement of the SMRT co-repressor in MM pathogenesis.