Transcriptional Functions and Targets of the MMSET Protein of t(4:14) Myeloma

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DESCRIPTION (provided by applicant): Multiple myeloma (MM) represents the malignant transformation of plasma cells, differentiated, post-germinal center B-cells adapted for the production of large quantities of antibody. Multiple myeloma is one of the commonest hematological malignancies and despite the advent of several new therapies such as proteosome inhibitors and thalidomide and the use of stem cell transplant consolidation, the disease is incurable with a median survival of about three years. The pathogenesis of this disease for many years was quite obscure, but over the past decade progress has been made based upon the characterization of consistent chromosomal translocations involving the immunoglobulin heavy chain (IgH). These translocations implicate particular genes in the pathogenesis of myeloma. MMSET (MULTIPLE MYELOMA SET DOMAIN) gene was identified at the breakpoint of the t(4;14) translocation, present in ~15% of multiple myeloma. This gene rearrangement leads to the transcriptional activation and overexpression of the FGFR3 gene and the MMSET gene, however in about 15% of cases only MMSET and not FGFR3 is overexpressed due to the rearrangement leading to the idea that deregulation of MMSET expression is central to the pathogenesis of this form of multiple myeloma. MMSET has a SET domain previously identified in histone methyl transferases and several other protein domains found in chromatin regulators. It has been confirmed that the MMSET protein is significantly overexpressed in myeloma cells harboring the t(4;14) translocation. The preliminary data indicates that MMSET has proprieties of a transcriptional co-factor, including localization to the nucleus, the ability to bind to sequence specific transcription factors including the zinc finger protein ZNF331 and transcriptional co-factors and histone deacetylases. In addition MMSET has histone methyl transferase activity which may be significantly different in terms of specificity when compared to other such proteins. These data lead to our overarching hypothesis that aberrant overexpression of MMSET leads to deregulated gene expression in B cells, contributing to the pathogenesis of myeloma. Our specific aims are: 1) To determine the transcriptional functions of MMSET, 2) To determine the biological activity of MMSET on Myeloma Cell Growth using gain of function and loss of function strategies, 3) To characterize the MMSET transcriptional complex and partner proteins for gene regulation, 4) To identify genes regulated by MMSET relevant to Multiple Myeloma. PUBLIC HEALTH RELEVANCE: MMSET protein is significantly overexpressed in myeloma cells harboring the t(4;14) translocation. These data lead to our overarching hypothesis that aberrant overexpression of MMSET leads to deregulated gene expression in B cells, contributing to the pathogenesis of myeloma.