The genomic pathogenesis of Follicular Lymphoma

滤泡性淋巴瘤的基因组发病机制

基本信息

批准号：
9002028
负责人：
Sami Nimer Malek
金额：
$ 54.2万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9002028
关键词：
Affect Alleles Amino Acids Anatomy Attention Automobile Driving B-Cell NonHodgkins Lymphoma Behavior Biological Models Cell Line Characteristics Chronic Lymphocytic Leukemia Clinical Code Codon Nucleotides DNA Binding Domain DNA Sequence Alteration Data Data Set Development Disease Disease remission EZH2 gene Epigenetic Process Follicular Lymphoma Future Gene Family Gene Mutation Genes Genetic study Genome Genomics Health Histone H1 Histone H1(s)Histones Incidence Life Lymphomagenesis Mantle Cell Lymphoma Modeling Molecular Mus Mutation Nucleotides Outcome POU2F2 gene Pathogenesis Pathway interactions Patients Recurrence Relapse Reporting Research Infrastructure Risk Role STAT6 gene Source Testing Therapeutic Transplantation base chromosome fusion cohort exome functional genomics genome sequencing genomic aberrations insight interest mouse model mutant novel novel therapeutics programs prospective structural genomics therapy development tool transcriptome sequencing whole genome

项目摘要

DESCRIPTION (provided by applicant): Follicular lymphoma (FL) constitutes the second most common B-cell Non-Hodgkin's lymphoma (B-NHL) with an annual incidence of ~14,000 cases and more than 100,000 patients in the US living with the disease. Despite improvements in the survival of FL patients, the disease remains incurable and patients go through cycles of treatment, remission and relapse. Targeted or risk-adapted FL therapies are not available or are substantially less active than in either chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL). Consequently, the societal health burden of FL is high. The majority of FL is characterized by the recurrent translocation t(14;18) resulting in increased expression of Bcl2 but this is neither sufficient nor necessary for FL development. Recently, novel inroads into the genomic pathogenesis of FL have been made and have resulted in a description of recurrent structural genomic alterations as well as recurrent gene mutations in FL. However, existing data are incomplete and comparatively little is known about functional or mechanistic consequences of these genomic aberrations. Importantly, FL still receives comparatively little scientific attention, and as a consequence, FL pathogenesis remains largely obscure. This reflects, at least in part that few centers have developed the translational infrastructure to study primary FLs and that accurate experimental tools to study FL have been lacking and all available cell lines are derived from transformed FLs. Over the last 7 years, we have developed the infrastructure to prospectively collect and analyze FLs and to correlate novel molecular findings with clinical characteristics and outcome and have undertaken genomic and functional approaches to dissect the pathogenesis of FL. In parallel, we have developed a genetically and pathologically accurate murine model of FL that enables rapid analysis of potential disease-driving mutant alleles. We have combined our complementary expertise to establish a program of functional genetic studies focused on FL. Our initial genomic studies, which will be expanded as part of this application, have yielded a rich source of novel candidate genomic FL drivers and these will now be tested for functional implications. We have reported that 27% of FL carry mutations in the linker histone H1 family of genes (HIST1H1-B-E) and that these mutations are largely mutually exclusive with mutations in EZH2 and ARID1A. We hypothesize that these mutations promote FL development through perturbation of either shared and/or alternate epigenetic pathways. Our exciting discovery of activating FL-associated STAT6 mutations forms the basis for detailed mechanistic studies as outlined in Aim 3. Overall, we will define how recurrently altered genes drive FL lymphomagenesis and will explore therapeutic opportunities resulting from these novel insights.

描述（由申请人提供）：滤泡性淋巴瘤 (FL) 是第二常见的 B 细胞非霍奇金淋巴瘤 (B-NHL)，每年发病约 14,000 例，在美国有超过 100,000 名患者患有该疾病。尽管 FL 患者的生存率有所改善，但该疾病仍然无法治愈，患者会经历治疗、缓解和复发的周期。与慢性淋巴细胞白血病 (CLL) 或套细胞淋巴瘤 (MCL) 相比，靶向或风险适应的 FL 疗法尚不可用，或者其活性大大降低。因此，FL 的社会健康负担很高。大多数 FL 的特征是反复易位 t(14;18) 导致 Bcl2 表达增加，但这对于 FL 的发展既不充分也不是必要的。最近，人们对 FL 的基因组发病机制取得了新的进展，并导致了对 FL 中反复出现的结构基因组改变以及反复出现的基因突变的描述。然而，现有数据并不完整，而且对这些基因组畸变的功能或机制后果知之甚少。重要的是，FL 受到的科学关注相对较少，因此，FL 发病机制在很大程度上仍然不清楚。这至少在一定程度上反映出，很少有中心开发出用于研究原代 FL 的转化基础设施，并且缺乏研究 FL 的准确实验工具，并且所有可用的细胞系均源自转化的 FL。在过去的 7 年里，我们开发了基础设施来前瞻性地收集和分析 FL，并将新的分子发现与临床特征和结果相关联，并采用基因组和功能方法来剖析 FL 的发病机制。与此同时，我们开发了一种遗传和病理学上准确的 FL 小鼠模型，能够快速分析潜在的疾病驱动突变等位基因。我们结合了互补的专业知识，建立了一个专注于 FL 的功能遗传学研究计划。我们最初的基因组研究（将作为该应用的一部分进行扩展）已经产生了丰富的新型候选基因组 FL 驱动程序，现在将测试这些驱动程序的功能含义。我们报道，27% 的 FL 携带接头组蛋白 H1 基因家族 (HIST1H1-B-E) 突变，并且这些突变在很大程度上与 EZH2 和 ARID1A 的突变是相互排斥的。我们假设这些突变通过扰动共享和/或替代的表观遗传途径来促进 FL 的发展。我们对激活 FL 相关 STAT6 突变的令人兴奋的发现构成了目标 3 中概述的详细机制研究的基础。总体而言，我们将定义反复改变的基因如何驱动 FL 淋巴瘤发生，并将探索从这些新见解中产生的治疗机会。