Disruption of epigenetic regulation of enhancers in the germinal center reaction drives clonal evolution in Follicular Lymphoma

生发中心反应中增强子表观遗传调控的破坏驱动滤泡性淋巴瘤的克隆进化

• 批准号: 10218056
• 负责人: Christopher Russell Chin
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2023-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218056
• 关键词: Accounting; Adaptive Immune System; Address; Affect; Affinity; American Cancer Society; Apoptosis; Apoptotic; Automobile Driving; B-Cell Antigen Receptor; B-Lymphocytes; BCL2 gene; Biological Assay; Bone Marrow; CREBBP gene; Cells; Cellular Assay; Chimera organism; Chromatin; Clonal Evolution; Clonal Expansion; Complex; Data; Development; Diagnosis; Disease; Enhancers; Epigenetic Process; Event; Follicular Lymphoma; Founder Generation; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genotype; Heterozygote; Histones; Human; IGH@ gene cluster; Immunoglobulin Somatic Hypermutation; Individual; Indolent; Lymphoma; Lymphoma cell; Lysine; Malignant - descriptor; Mediating; Methyltransferase; Modeling; Mus; Mutation; Nature; Non-Hodgkin' s Lymphoma; Nonsense Mutation; Patient Monitoring; Point Mutation; Process; Reaction; Recycling; Reporting; Role; Sampling; Somatic Mutation; Structure of germinal center of lymph node; Symptoms; Time; XCL1 gene; base; clinical practice; differential expression; epigenetic regulation; histone acetyltransferase; histone methyltransferase; human disease; large cell Diffuse non-Hodgkin' s lymphoma; loss of function; mouse model; prevent; programs; stem; tumor

PROJECT SUMMARY/ABSTRACT Follicular Lymphoma (FL) is the second most common form of non-Hodgkin's lymphoma, accounting for 20- 30% of non-Hodgkin's lymphoma diagnoses. Though FL is an indolent disease, it eventually transforms into more aggressive, incurable forms of lymphoma. FL is hallmarked by the anti-apoptotic IGH/BCL2 translocation, which is often accompanied by a mutation in an epigenetic gene. Here, we propose to investigate the roles of these mutations in epigenetic genes, specifically KMT2D and CREBBP due to their high rate of occurrence, in the development and transformation process of FL. In our first aim, we plan to use mixed bone marrow chimera mouse models to determine the role of these mutations in driving early clonal evolution of the disease. In our second aim, we plan to then characterize the gene expression and chromatin accessibility of the resulting lymphoma to determine how these mutations cooperate to drive progression through epigenetic reprogramming of the tumor.

项目总结/文摘