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

项目概要/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%的非霍奇金淋巴瘤诊断。虽然FL是一种惰性疾病，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IGH/BCL 2易位， 这通常伴随着表观遗传基因的突变。在这里，我们建议调查的作用， 表观遗传基因中的这些突变，特别是KMT 2D和CREBBP，由于它们的高发生率， FL的发生和转化过程。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，以确定这些突变在驱动疾病早期克隆进化中的作用。在我们 第二个目标，我们计划然后表征基因表达和染色质可及性的结果， 淋巴瘤，以确定这些突变如何合作，通过表观遗传重编程推动进展 肿瘤。

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.