The genomic pathogenesis of Follicular Lymphoma

描述(申请人提供)：滤泡性淋巴瘤(FL)是第二常见的B细胞性非霍奇金淋巴瘤(B-NHL)，在美国每年的发病率约为14,000例，有超过100,000名患者患有这种疾病。尽管FL患者的存活率有所改善，但这种疾病仍然是无法治愈的，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，靶向或风险适应FL疗法不可用或活性显著降低。因此，FL的社会健康负担很高。大多数FL的特点是反复易位t(14；18)，导致bcl2表达增加，但这对FL的发展既不充分也不必要。最近，在FL的基因组发病机制方面取得了新的进展，并导致了FL中复发的结构基因组改变和复发的基因突变的描述。然而，现有的数据是不完整的，对这些基因组异常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的发病机制仍然很不清楚。这至少在一定程度上反映出，很少有中心开发出研究原代FL的翻译基础设施，而且一直缺乏研究FL的准确实验工具，所有可用的细胞系都是从转化的FL衍生而来的。在过去的7年里，我们已经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。同时，我们开发了一种在遗传学和病理学上准确的FL小鼠模型，使快速分析潜在的致病突变等位基因成为可能。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这一应用的一部分进行扩展，已经产生了丰富的候选基因组FL驱动程序，现在将测试这些驱动程序的功能。我们已经报道了27%的FL携带连接物组蛋白H1家族基因(HIST1H1-B-E)的突变，并且这些突变在很大程度上与EZH2和ARID1A的突变互斥。我们假设这些突变通过扰乱共享和/或交替的表观遗传途径来促进FL的发展。我们激动人心的发现激活FL相关的STAT6突变，为目标3中概述的详细机制研究奠定了基础。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，并将探索这些新见解带来的治疗机会。

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.