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.

项目摘要/摘要 卵泡淋巴瘤（FL）是非霍奇金淋巴瘤的第二大最常见形式，占20- 非霍奇金淋巴瘤诊断的30％。尽管FL是一种懒惰的疾病，但它最终转化为 更具侵略性，无法治愈的淋巴瘤形式。 FL是由抗凋亡IGH/BCL2易位标志的 通常伴随着表观遗传基因中的突变。在这里，我们建议调查 这些突变在表观遗传基因中，特别是KMT2D和CREBBP，因为它们的发生率很高 FL的发展和转变过程。在我们的第一个目标中，我们计划使用混合的骨髓嵌合体 小鼠模型确定这些突变在驱动疾病早期克隆进化中的作用。在我们的 第二个目的，我们计划表征所得的基因表达和染色质可及性 淋巴瘤确定这些突变如何通过表观遗传重编程驱动进展 肿瘤。