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

描述（由申请方提供）：多发性骨髓瘤（MM）代表浆细胞的恶性转化，分化的后生殖中心B细胞适应于产生大量抗体。多发性骨髓瘤是最常见的血液恶性肿瘤之一，尽管出现了几种新的治疗方法，如蛋白酶体抑制剂和沙利度胺以及使用干细胞移植巩固，但该疾病无法治愈，中位生存期约为三年。这种疾病的发病机制多年来是相当模糊的，但在过去的十年中，已经取得了进展的基础上一致的染色体易位涉及免疫球蛋白重链（IgH）的表征。这些易位涉及骨髓瘤发病机制中的特定基因。MMSET（多发性骨髓瘤SET域）基因在t（4;14）易位的断点处被鉴定，存在于约15%的多发性骨髓瘤中。这种基因重排导致FGFR 3基因和MMSET基因的转录激活和过表达，然而，在大约15%的病例中，由于重排，只有MMSET而不是FGFR 3过表达，这导致了MMSET表达失调是发病机制的核心的想法。这种形式的多发性骨髓瘤。MMSET具有先前在组蛋白甲基转移酶中鉴定的SET结构域和在染色质调节剂中发现的几个其他蛋白质结构域。已经证实，MMSET蛋白在携带t（4;14）易位的骨髓瘤细胞中显著过表达。初步数据表明，MMSET具有转录辅因子的特性，包括定位于细胞核，能够结合序列特异性转录因子，包括锌指蛋白ZNF 331和转录辅因子和组蛋白脱乙酰酶。此外，MMSET具有组蛋白甲基转移酶活性，当与其他这样的蛋白质相比时，其在特异性方面可能显著不同。这些数据导致我们的总体假设，即MMSET的异常过表达导致B细胞中基因表达失调，导致骨髓瘤的发病机制。我们的具体目标是：1）确定MMSET的转录功能; 2）使用功能获得和功能丧失策略确定MMSET对骨髓瘤细胞生长的生物学活性; 3）表征MMSET转录复合物和基因调控的伴侣蛋白; 4）鉴定MMSET调控的多发性骨髓瘤相关基因。公共卫生相关性：MMSET蛋白在携带t（4;14）易位的骨髓瘤细胞中显著过表达。这些数据导致我们的总体假设，即MMSET的异常过表达导致B细胞中基因表达失调，导致骨髓瘤的发病机制。

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.