UTX, MLL and Pathogenic Deregulation of Histone Methylation in Multiple Myeloma

多发性骨髓瘤中组蛋白甲基化的 UTX、MLL 和致病性失调

• 批准号: 8775116
• 负责人: Jonathan D. Licht
• 金额: $ 37.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775116
• 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; Clinical; 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; Modification; Multiple Myeloma; Mus; Mutate; Mutation; Names; Oncogenes; Pathogenesis; 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; gain of function; gain of function mutation; gene repression; genome sequencing; genome-wide; histone acetyltransferase; histone methyltransferase; histone modification; inhibitor/antagonist; leukemia; loss of function; loss of function mutation; member; methyl group; novel; novel therapeutic intervention; overexpression; pre-clinical; promoter; protein complex; public health relevance; research study; response; 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）：基因组测序的进展表明，染色质调节剂中的复发突变是恶性肿瘤中的常见特征，包括多发性骨髓瘤（MM）。在这些病变中，组蛋白甲基转移酶（HMT）和组蛋白脱甲基酶的突变是突出的。这些突变可能会产生染色质的全球全基因组功能障碍，强烈影响基因调节，并可能影响其他染色质依赖性过程。组蛋白3赖氨酸27三甲基化（H3K27me3）与基因沉默和H3K4甲基化相关的平衡与基因激活有关，对于正常基因表达至关重要。 PRC2复合物（PolyComb抑制复合物2）在其核心A H3K27-Specifc HMT，EZH2。 EZH2或伴侣蛋白（例如ASXL1）的功能突变丧失导致H3K27ME3的全球损失，而淋巴瘤中EZH2功能突变的增益增加了H3K27ME3。通过在小儿脑肿瘤中发现H3K27-> M突变的强调，这种残留物的重要性，排除组蛋白修饰20并阻止EZH2动作21。此外，我们发现MMSET的过度表达，H3K36特异性的HMT在MM中导致基因对基因组较高的H3K27逐渐减少H3K27ME3K27Me n3K27Me n3K27Me n3K27Me n3K27Me。基因激活需要去除H3K27标记，并在基因启动子和增强子上进行H3K4ME修饰的位置。这是通过含有H3K27-特异性组蛋白脱甲基酶UTX（普遍转录的四肽重复转录，X染色体）的多蛋白质复合物，MLL（混合谱系白血病）HMTS的成员（包括MLL2和MLL2和MLL3）的成员（包括MLL2和MLL3），组合乙基糖酶p3 ant anf p3 snev和CREBB300和CREB300和CREB300染色质重塑机械。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。具体而言，UTX（官方基因名称KDM6A）在多达30％的MM中被突变或删除。此外，MLL2，尤其是MLL3在MM中显示失活的突变。我们假设UTX和MLL3突变在MM发病机理中具有相似的功能，从而导致H3K27ME/H3K4ME的异常失衡和关键靶基因的抑制。因此，在临床前和早期临床发育中，H3K27甲基化降低的EZH2抑制剂可能能够重新平衡染色质的修饰并提供一种新的治疗方法。为了测试这些想法，我们提出以下具体目的：1）确定UTX和MLL3在控制染色质结构，MM和淋巴样细胞的染色质结构，细胞生长和稳态中的重要性2）确定MM 3）确定UTX和MLL3在MM 3）中的遗传靶标和途径的重要性。