The genomic pathogenesis of Follicular Lymphoma

滤泡性淋巴瘤的基因组发病机制

• 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
• 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

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），在美国每年的发病率约为14,000例，超过100,000例患者患有该疾病。尽管FL患者的生存率有所提高，但这种疾病仍然无法治愈，患者经历了治疗、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，靶向或适应风险的FL治疗方法不可用，或者活性低得多。因此，FL的社会健康负担很高。大多数FL的特征是复发性易位t(14;18)，导致Bcl2表达增加，但这对于FL的发展既不是充分的也不是必要的。最近，对FL的基因组发病机制有了新的研究进展，并对FL中复发性结构基因组改变和复发性基因突变进行了描述。然而，现有的数据不完整，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仍然受到相对较少的科学关注，因此，FL的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，很少有中心开发了研究原代FL的转化基础设施，并且缺乏研究FL的准确实验工具，而且所有可用的细胞系都来自转化的FL。在过去的7年里，我们已经开发了前瞻性收集和分析FL的基础设施，并将新的分子发现与临床特征和结果联系起来，并采用基因组和功能方法来解剖FL的发病机制。同时，我们已经开发了FL的遗传和病理精确的小鼠模型，能够快速分析潜在的疾病驱动突变等位基因。我们已经将我们的互补专业知识结合起来，建立了一个专注于FL的功能遗传学研究项目。我们最初的基因组研究，将作为该应用的一部分扩展，已经产生了丰富的新型候选基因组FL驱动源，现在将对这些驱动源进行功能影响测试。我们已经报道27%的FL携带连接蛋白H1家族基因（HIST1H1-B-E）突变，这些突变与EZH2和ARID1A的突变在很大程度上是互斥的。我们假设这些突变通过干扰共享和/或交替的表观遗传途径促进FL的发展。我们激动人心的发现激活fl相关的STAT6突变，为Aim 3中概述的详细机制研究奠定了基础。总的来说，我们将定义反复改变的基因是如何驱动FL淋巴瘤发生的，并将从这些新见解中探索治疗机会。