Trageting the Multiple Myeloma Epigenome

瞄准多发性骨髓瘤表观基因组

• 批准号: 8607272
• 负责人: JAMES E BRADNER
• 金额: $ 24.01万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-16 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607272
• 关键词: Activator Appliances; Award; B-Lymphocytes; BRD2 gene; Biological; Biology; Bromodomain; Cells; Chemicals; Chromatin; Clinical; Complex; Development; Disease; Drug resistance; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Global Change; Histones; Immunoglobulins; Instruction; Laboratories; Lead; Life; Link; Lysine; Methylation; Methyltransferase; Molecular Target; Multiple Myeloma; Mutate; Oncogenic; Pathogenesis; Patients; Plasma Cells; Production; Proliferating; Property; Protein Family; Proteins; Research; Role; Sequence Analysis; Signal Transduction; Specificity; Structure; Structure of germinal center of lymph node; TF gene; Therapeutic; Therapeutic Uses; Time; Tissues; Translating; Translations; base; c-myc Genes; differentiated B cell; epigenome; histone modification; inhibitor/antagonist; interest; outcome forecast; overexpression; programs; promoter; therapeutic target; transcription factor

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.

多发性骨髓瘤 (MM) 代表终末分化 B 细胞的持续增殖。多发性细胞 具有正常浆细胞的特性，例如高蛋白产量和耐寒性，但不同之处在于 尽管MM细胞处于终末分化状态，但仍继续增殖并表达c-Myc。这 MM 的增殖程序由转录因子和染色质相关因子协调。 MYC、NFGB、MAF 和 XBP1 等转录因子与疾病发病机制、组织相关 特异性和耐药性。其中一些因子通过异常连锁在 MM 中过度表达 免疫球蛋白启动子与TF基因的连接。此外，MM基因组的序列分析 研究表明，在 MM 突变或缺失的基因中，染色质的比例过高 监管因素。组蛋白甲基化在 MM 中的中心地位是通过以下发现得到牢固确立的： 赖氨酸甲基转移酶 (MMSET) 在预后不良的 t(4;14) 相关 MM 中重排并激活。 我们小组和其他人的其他研究发现 MM 增殖依赖于溴结构域 和蛋白质的额外末端 (BET) 结构域家族（BRD2、BRD3 和 BRD4）及其支持 c-MYC 的转录程序。这些发现共同创造了我们的中心假设：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目标。建立在 由于我们对染色质生物学的共同兴趣，我们开展了一项合作计划来研究和瞄准 MM 中的 BRD4 和 MMSET。假设：Myc 在分化的浆细胞中异常过度表达 仍然是 MM 的核心悖论和驱动力。转录信号是发病机制的基础 MM 的形成需要 BET 溴结构域的共激活剂功能。直接抑制 BET 溴结构域 单独使用或联合使用构成了 MM 的强大治疗策略。 MMSET 赖氨酸 甲基转移酶与 BRD4 复合，通过整体刺激骨髓瘤发病机制 组蛋白修饰和基因表达的变化。 MMSET 的致癌活性与 其组蛋白甲基化活性以及 MMSET 和 BRD4 代表了引人注目的分子靶点 开发新的 MM 疗法。我们将追求以下具体目标： 目标 1. 描述 Myc 和 E2F 转录程序的表观遗传书签中的 BET 溴结构域。目标 2. 研究 MMSET 域适合于治疗靶向，由晶体结构引导，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。