Role of MEF2B mutations in lymphomagenesis

MEF2B 突变在淋巴瘤发生中的作用

• 批准号: 8697703
• 负责人: Riccardo Dalla-Favera
• 金额: $ 44.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697703
• 关键词: Affect; Alleles; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; BCL2 gene; BCL6 gene; Binding; Biochemical; Cells; ChIP-seq; Chromosomal translocation; Cyclic AMP-Dependent Protein Kinases; DNA-Protein Interaction; Data; Data Set; Development; Disease; Engineering; Follicular Lymphoma; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Human; Knock-in Mouse; Lesion; Lymphoid; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Missense Mutation; Modeling; Modification; Molecular; Molecular Profiling; Mus; Mutate; Mutation; N-terminal; Oncogenic; Organ; Other Genetics; Pathogenesis; Patients; Pattern; Phenotype; Phosphorylation; Proteins; Proto-Oncogenes; Reaction; Receptors, Antigen, B-Cell; Regulation; Research Proposals; Role; Signal Pathway; Structure of germinal center of lymph node; TNFRSF5 gene; Testing; Transcription Coactivator; Transgenic Mice; Treatment Protocols; base; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; mutant; programs; promoter; protein complex; public health relevance; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to functionally characterize MEF2B, a transcription factor that has been recently identified as a master regulator of the germinal center (GC) reaction and whose genomic locus is targeted by activating mutations in Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL), the two most common forms of human lymphoma. The MEF2B gene encodes a transcriptional activator and is found mutated in ~11% of diffuse large B-cell lymphomas (DLBCL) and ~12% of follicular lymphomas. We have shown that MEF2B directly activates the transcription of the proto-oncogene BCL6 in normal germinal center (GC) B cells and is required for DLBCL proliferation. MEF2B mutations enhance MEF2B transcriptional activity either by disrupting its interaction with the co-repressor CABIN1, or by rendering it insensitive to the inhibitory effects f PKA-mediated phosphorylation and sumoylation. Consequently, BCL6 transcriptional activity is deregulated in DLBCL harboring MEF2B mutations. Based on these initial results, this research proposal aims at investigating the role of MEF2B as modulator of GC development and lymphomagenesis. In particular, the following specific aims will be pursued: 1) determine the role of MEF2B in normal GC development by i) analyzing the phenotype of mice carrying conditional, GC-specific inactivation of MEF2B, ii) identifying the MEF2B target genes by ChIP-seq, and iii) the proteins that regulate MEF2B activity in GC B cells by mass spectrometry analysis; 2) functionally characterize the MEF2B mutations identified in DLBCL and FL, including both the N-terminus missense mutants that affect transcriptional co-repressor binding and the C- terminus truncating mutations that affect its negative regulation by phosphorylation and/or sumoylation; 3) determine the consequences of MEF2B mutations in vivo by analyzing transgenic mice with conditional activation of mutant MEF2B alleles in GC B cells, alone or in combination with other mutations co-existing in DLBCL and FL.

描述（由申请人提供）：本研究计划的总体目标是对 MEF2B 进行功能表征，MEF2B 是一种转录因子，最近被确定为生发中心 (GC) 反应的主要调节因子，其基因组位点是通过激活弥漫性大 B 细胞淋巴瘤 (DLBCL) 和滤泡性淋巴瘤 (FL)（人类淋巴瘤的两种最常见形式）中的突变来靶向的。 MEF2B 基因编码转录激活因子，在约 11% 的弥漫性大 B 细胞淋巴瘤 (DLBCL) 和约 12% 的滤泡性淋巴瘤中发现突变。我们已经证明 MEF2B 直接激活正常生发中心 (GC) B 细胞中原癌基因 BCL6 的转录，并且是 DLBCL 增殖所必需的。 MEF2B 突变通过破坏 MEF2B 与共阻遏物 CABIN1 的相互作用，或使其对 PKA 介导的磷酸化和苏酰化的抑制作用不敏感，从而增强 MEF2B 转录活性。因此，在携带 MEF2B 突变的 DLBCL 中，BCL6 转录活性失调。基于这些初步结果，本研究计划旨在研究 MEF2B 作为 GC 发展和淋巴瘤发生调节剂的作用。具体而言，将追求以下具体目标：1) 通过 i) 分析携带 MEF2B 条件性 GC 特异性失活的小鼠的表型，ii) 通过 ChIP-seq 鉴定 MEF2B 靶基因，以及 iii) 通过质谱分析调节 GC B 细胞中 MEF2B 活性的蛋白质，确定 MEF2B 在正常 GC 发育中的作用； 2) 对DLBCL和FL中鉴定的MEF2B突变进行功能表征，包括影响转录共阻遏物结合的N端错义突变体和通过磷酸化和/或苏酰化影响其负调节的C端截短突变； 3) 通过分析GC B细胞中突变MEF2B等位基因的条件激活（单独或与DLBCL和FL中共存的其他突变组合）的转基因小鼠，确定MEF2B突变在体内的后果。