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（由申请方提供）：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），在美国每年约有14，000例病例和超过100，000例患者患有该疾病。尽管FL患者的生存率有所改善，但该疾病仍然无法治愈，患者经历治疗，缓解和复发的周期。靶向或风险适应性FL疗法不可用，或活性远低于慢性淋巴细胞白血病（CLL）或套细胞淋巴瘤（MCL）。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Bcl 2表达增加，但这对于FL的发展既不充分也不必要。最近，新的进展到FL的基因组发病机制已经取得，并导致在描述经常性的结构基因组改变以及经常性的基因突变FL。然而，现有的数据是不完整的，相对较少的是已知的功能或机制的后果，这些基因组畸变。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。这至少部分反映了很少有中心开发了研究初级FL的翻译基础设施，并且缺乏研究FL的准确实验工具，并且所有可用的细胞系都来自转化的FL。在过去的7年里，我们已经开发了基础设施，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，并采取了基因组和功能方法来剖析FL的发病机制。同时，我们已经开发了一种遗传和病理学上准确的FL小鼠模型，可以快速分析潜在的疾病驱动突变等位基因。 我们结合了我们互补的专业知识，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，将作为本申请的一部分进行扩展，已经产生了丰富的新候选基因组FL驱动程序，现在将对这些驱动程序进行功能测试。我们已经报道了27%的FL携带连接体组蛋白H1基因家族（HIST 1H 1-B-E）的突变，并且这些突变在很大程度上与EZH 2和ARID 1A中的突变相互排斥。我们推测，这些突变促进FL的发展，通过干扰共享和/或替代表观遗传途径。我们激动人心的发现激活FL相关的STAT 6突变形成了详细的机制研究的基础，如目标3所述。总的来说，我们将定义如何反复改变基因驱动FL淋巴瘤的发生，并将探索从这些新的见解产生的治疗机会。