Trageting the Multiple Myeloma Epigenome

多发性骨髓瘤(MM)代表终末分化的B细胞持续增殖。MM细胞 与正常浆细胞具有相同的特性，如高蛋白产生和坚韧，但不同之处在于 MM细胞尽管处于终末分化状态，但仍继续增殖并表达c-Myc。这个 多发性骨髓瘤的增殖过程受转录因子和染色质相关因子的调节。 转录因子如MYC、NFGB、MAF和XBP1与疾病的发病机制、组织 特异性和抗药性。其中一些因子通过异常连锁在多发性骨髓瘤中过度表达 免疫球蛋白启动子对转铁蛋白基因的影响。此外，MM基因组的序列分析 揭示在多发性骨髓瘤中突变或缺失的基因中存在染色质的过度表达 监管因素。组蛋白甲基化在多发性骨髓瘤中的中心地位被牢固地建立在一个发现上 赖氨酸甲基转移酶(MMSET)在预后不良的t(4；14)相关MM中被重排和激活。 我们小组和其他人的进一步研究发现，MM的增殖依赖于溴域 和超末端(BET)结构域蛋白家族(BRD2、BRD3和BRD4)及其支持 C-myc转录程序。这些发现共同创造了我们的中心假设，即异常基因 调节是多发性骨髓瘤生物学的基础，这些异常可以作为治疗靶点。在基础上建设 我们对染色质生物学的共同兴趣，我们已经开展了一个合作项目来研究和瞄准 MM中的BRD4和MMSET假说：Myc在分化的浆细胞中异常过表达 仍然是MM的核心悖论和驱动力，转录信号是MM发病机制的基础 对于MM，需要BET溴域的共激活功能。BET溴域的直接抑制作用 单独和联合治疗MM是一种有效的治疗策略，MMSET赖氨酸 甲基转移酶与BRD4形成复合体，通过全球 组蛋白修饰和基因表达的变化。MMSET的致癌活性与 它的组蛋白甲基化活性以及MMSET和BRD4代表着引人注目的分子靶点 开发新的多发性骨髓瘤疗法。我们将追求以下具体目标：目标1.确定 在Myc和E2F转录程序的表观遗传书签中加入BET溴域。目的2.研究 适用于治疗靶向的MMSET结构域，由晶体结构指导，并开发 MMSET抑制剂作为化学探针和铅治疗药物。目的3.翻译BET和MMSET抑制剂 MM患者的治疗应用。

Multiple myeloma (MM) represents the continued proliferation of a terminal differentiated B cell. MM cells share the properties of normal plasma cells such as high protein production and hardiness but differ in that MM cells continue to proliferate and express c-Myc despite their terminal differentiated state. The proliferative program of MM is coordinated by transcription factors and chromatin-associated factors. Transcription factors such as MYC, NFGB, MAF and XBP1 are linked to disease pathogenesis, tissue specificity, and drug resistance. Several of these factors are overexpressed in MM through aberrant linkage of the immunoglobulin promoter to the TF gene. Furthermore, sequence analysis of the MM genome revealed that amongst the genes mutated or deleted in MM, there is over-representation of chromatin regulatory factors. The centrality of histone methylation in MM was firmly established by the discovery that a lysine methyltransferase (MMSET) is rearranged and activated in poor prognosis t(4;14)-associated MM. Additional research from our group and others found that MM proliferation is dependent on the bromodomain and extra-terminal (BET) domain family of proteins (BRD2, BRD3 and BRD4) and their ability to support the transcriptional program of c-MYC. Together these findings create our central hypothesis that aberrant gene regulation underlies the biology of MM, and that these anomalies can be therapeutically targeted. Building on our mutual interest in chromatin biology, we have undertaken a collaborative program to study and target BRD4 and MMSET in MM. Hypotheses: Aberrant overexpression of Myc in a differentiated plasma cell remains a central paradox of and driver of MM. Transcriptional signaling, which underlies the pathogenesis of MM, requires the co-activator function of BET bromodomains. Direct inhibition of BET bromodomains alone and in combination comprises a powerful therapeutic strategy in MM. The MMSET lysine methyltransferase, which is found in complex with BRD4, stimulates myeloma pathogenesis through global changes in histone modification and gene expression. The oncogenic activity of MMSET is closely linked to its histone methylation activity and MMSET and BRD4 represent compelling molecular targets for development of new MM therapies. We will pursue following Specific Aims: Aim 1. To characterize the role of BET bromodomains in epigenetic bookmarking of the Myc and E2F transcriptional programs.Aim 2. To study domains of MMSET amenable for therapeutic targeting, guided by crystallographic structures, and develop MMSET inhibitors as chemical probes and lead therapeutics. Aim 3. To translate BET and MMSET inhibitors to therapeutic use in patients with MM.