UTX, MLL AND PATHOGENIC DEREGULATION OF HISTONE METHYLATION IN MULTIPLE MYELOMA

多发性骨髓瘤中的 UTX、MLL 和组蛋白甲基化的致病性失调

• 批准号: 9353181
• 负责人: Jonathan D. Licht
• 金额: $ 34.74万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353181
• 关键词: ATP phosphohydrolase; Adhesions; Affect; B-Cell Development; B-Lymphocytes; Biological Process; CREBBP gene; Cell Line; Cell Maturation; Cells; ChIP-seq; Chemicals; Childhood Brain Neoplasm; Chromatin; Chromatin Structure; Complex; DNA; DNA Damage; Data Set; Development; EP300 gene; EZH2 gene; Enhancers; Equilibrium; Excision; Family; Family member; Functional disorder; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Genetic; Growth and Development function; Histone Acetylation; Histones; Homeostasis; Human; Immune system; Lead; Lesion; Link; Lymphocyte; Lymphoid Cell; Lymphoma; Lysine; MLL2 gene; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Methylation; Mixed-Lineage Leukemia; Modification; Multiple Myeloma; Multiprotein Complexes; Mus; Mutate; Mutation; Names; Oncogenes; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Physical condensation; Polycomb; Process; Proteins; Proteomics; Recurrence; Specimen; Structure of germinal center of lymph node; System; Testing; Tumor Suppressor Proteins; Tumorigenicity; X Chromosome; c-myc Genes; cell growth; chemotherapy; chromatin modification; chromatin remodeling; clinical development; experimental study; gain of function; gain of function mutation; gene repression; genome sequencing; genome-wide; histone acetyltransferase; histone demethylase; histone methylation; histone methyltransferase; histone modification; inhibitor/antagonist; loss of function; loss of function mutation; member; methyl group; novel; novel therapeutic intervention; overexpression; pre-clinical; promoter; protein complex; public health relevance; response; therapeutic target; transcriptome sequencing; tumor

DESCRIPTION (provided by applicant): Advances in genome sequencing revealed that recurrent mutations in chromatin regulators are a common feature in malignancy, including multiple myeloma (MM). Among these lesions, mutations in histone methyltransferases (HMTs) and histone demethylases are prominent. These mutations may yield global, genome-wide dysfunction of chromatin, strongly affecting gene regulation and possibly influencing other chromatin-dependent processes. The balance between histone 3 lysine 27 trimethylation (H3K27me3), associated with gene silencing and H3K4 methylation, linked to gene activation, is critical for normal gene expression. The PRC2 complex (Polycomb Repressive Complex 2) contains at its core a H3K27-specifc HMT, EZH2. Loss of function mutations of EZH2 or partner proteins such as ASXL1 lead to global loss of H3K27me3, while gain of function mutations of EZH2 in lymphoma increases H3K27me3. The importance of this residue was underscored by discovery of H3K27->M mutation in pediatric brain tumors, precluding histone modification 20 and blocking EZH2 action 21. Furthermore, we found that overexpression of MMSET, an H3K36-specific HMT, in MM causes a genome-wide decrease in H3K27me3. Gene activation requires the removal of the H3K27 mark and placement of the H3K4me modification at gene promoters and enhancers. This is accomplished by a multi-protein complex containing the H3K27- specific histone demethylase UTX, (Ubiquitously transcribed Tetratricopeptide repeat, X chromosome), members of the MLL (Mixed Lineage Leukemia) family of HMTs (including MLL2 and MLL3), histone acetyltransferases p300 and CREBBP, and members of the SWI/SNF chromatin remodeling machinery. Almost all members of these complexes can be mutated in lymphoid malignancies. Specifically, UTX (Official gene name KDM6A) is mutated or deleted in up to 30% of MM. Moreover, MLL2 and especially MLL3 display inactivating mutations in MM. We hypothesize that UTX and MLL3 mutations have a similar function in MM pathogenesis to cause an aberrant imbalance of H3K27me/H3K4me and suppression of critical target genes. Accordingly, an EZH2 inhibitor that decreases H3K27 methylation is in preclinical and early clinical development may be able to rebalance chromatin modifications and offer a new therapeutic approach. To test these ideas we propose the following specific Aims: 1) Determine the Importance of UTX and MLL3 in the Control of Chromatin Structure, Cell Growth and Homeostasis of MM and Lymphoid Cells 2) Determine the Genetic Targets and Pathways Affected by Loss of UTX and MLL3 in MM 3) Determine the Importance of UTX in B Cell Maturation and in the Development of MM

描述（由申请人提供）：基因组测序的进展显示，染色质调节因子的复发性突变是恶性肿瘤（包括多发性骨髓瘤（MM））的常见特征。在这些病变中，组蛋白甲基转移酶（HMT）和组蛋白去甲基化酶的突变是突出的。这些突变可能导致染色质的全基因组功能障碍，强烈影响基因调控，并可能影响其他染色质依赖性过程。与基因沉默相关的组蛋白3赖氨酸27三甲基化（H3 K27 me 3）和与基因激活相关的H3 K4甲基化之间的平衡对于正常基因表达至关重要。PRC 2复合物（Polycomb Repressive Complex 2）在其核心含有H3 K27特异性HMT，EZH 2。EZH 2或配偶体蛋白如ASXL 1的功能缺失突变导致H3 K27 me 3的整体缺失，而淋巴瘤中EZH 2的功能获得突变增加H3 K27 me 3。在儿科脑肿瘤中发现H3 K27->M突变，排除组蛋白修饰20和阻断EZH 2作用21，强调了该残基的重要性。此外，我们发现MM中MMSET（一种H3 K36特异性HMT）的过表达导致H3 K27 me 3的全基因组减少。基因激活需要去除H3 K27标记并在基因启动子和增强子处放置H3 K4 me修饰。这是通过含有H3 K27特异性组蛋白去甲基化酶UTX（遍在转录的三肽重复序列，X染色体）、HMT的MLL（混合谱系白血病）家族成员（包括MLL 2和MLL 3）、组蛋白乙酰转移酶p300和CREBBP以及SWI/SNF染色质重塑机制成员的多蛋白复合物来实现的。这些复合物的几乎所有成员都可以在淋巴恶性肿瘤中突变。此外，MLL 2，特别是MLL 3在MM中显示失活突变。我们假设UTX和MLL 3突变在MM发病机制中具有相似的功能，导致H3 K27 me/H3 K4 me的异常失衡和关键靶基因的抑制。因此，降低H3 K27甲基化的EZH 2抑制剂处于临床前和早期临床开发中，可能能够重新平衡染色质修饰并提供新的治疗方法。为了测试这些想法，我们提出了以下具体目标：1）确定UTX和MLL 3在MM和类肉瘤细胞的染色质结构、细胞生长和稳态控制中的重要性2）确定MM中受UTX和MLL 3缺失影响的遗传靶标和途径3）确定UTX在B细胞成熟和MM发展中的重要性