Targeting the Multiple Myeloma Epigenome

多发性骨髓瘤（MM）代表终末分化的B细胞的持续增殖。MM细胞 它们具有正常浆细胞的特性，例如高蛋白质产量和耐寒性，但不同之处在于， MM细胞继续增殖并表达c-Myc，尽管它们处于终末分化状态。的 MM的增殖程序由转录因子和染色质相关因子协调。 转录因子如MYC、NFGB、MAF和XBP 1与疾病的发病机制、组织病理学和免疫学有关。 特异性和耐药性。这些因子中的一些通过异常连锁在MM中过表达 免疫球蛋白启动子转移到TF基因上。此外，MM基因组的序列分析 揭示了在MM中突变或缺失的基因中， 调节因素。组蛋白甲基化在MM中的中心地位是通过以下发现牢固确立的： 赖氨酸甲基转移酶（MMSET）在预后不良的t（4;14）相关MM中重排和激活。 我们小组和其他人的额外研究发现，MM增殖依赖于布罗莫结构域， 和额外的末端（BET）结构域家族的蛋白质（BRD 2，BRD 3和BRD 4）和它们的能力，以支持 c-MYC的转录程序。这些发现共同创造了我们的核心假设，即异常基因 这些异常是MM生物学的基础，并且这些异常可以在治疗上靶向。基础上 我们在染色质生物学方面的共同兴趣，我们已经开展了一项合作计划， MM中BRD 4和MMSET的关系：Myc在分化浆细胞中异常过表达的假说 仍然是MM的核心矛盾和驱动因素。转录信号传导是发病机制的基础， MM的共活化剂需要BET溴结构域的共活化剂功能。BET溴结构域的直接抑制 MMSET赖氨酸单独和组合包含MM中的强大治疗策略。 与BRD 4复合的甲基转移酶，通过全球性的免疫反应刺激骨髓瘤的发病机制。 组蛋白修饰和基因表达的变化。MMSET的致癌活性与以下因素密切相关： 它的组蛋白甲基化活性和MMSET和BRD 4代表了令人信服的分子靶点， 开发新的MM疗法。我们将追求以下具体目标：目标1。描述的角色 BET布罗莫结构域在Myc和E2 F转录程序的表观遗传书签中的应用。研究 MMSET的结构域适合于治疗靶向，由晶体结构指导，并开发 MMSET抑制剂作为化学探针和先导疗法。目标3。翻译BET和MMSET抑制剂 MM患者的治疗用途。

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.