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

项目摘要/摘要 滤泡性淋巴瘤(FL)是第二种最常见的非霍奇金淋巴瘤，占20%- 30%的非霍奇金淋巴瘤的诊断。虽然FL是一种迟钝的疾病，但它最终会转化为 更具侵袭性的、无法治愈的淋巴瘤。FL的特点是抗凋亡的IgH/BCL2易位， 这通常伴随着表观遗传基因的突变。在这里，我们建议调查一下 这些表观遗传基因的突变，特别是KMT2D和CREBBP，由于其高发生率，在 外语教学的发展演变过程。在我们的第一个目标中，我们计划使用混合骨髓嵌合体 小鼠模型，以确定这些突变在推动疾病早期克隆进化中的作用。在我们的 第二个目的是，我们计划然后表征由此产生的基因表达和染色质的可及性 确定这些突变如何通过表观遗传重新编程协同推动淋巴瘤进展 肿瘤的组织结构。

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.