Genetic Basis of Signaling Heterogeneity in Human Follicular Lymphoma

描述(申请人提供)：滤泡性淋巴瘤(FL)通常是一种不治之症。在每一种情况下，肿瘤都是由具有独特的B细胞抗原受体(BCR)的B细胞克隆群体组成的。我们最近发现，在诊断时，每个FL肿瘤都含有通过其B细胞抗原受体(1)具有缺陷信号的肿瘤细胞亚群。这种对BCR不敏感的肿瘤亚群的大小随着时间的推移而扩大，它预示着对化疗的反应较差，总体生存时间较短。因此，我们提出了这样一个问题：滤泡性淋巴瘤的两种肿瘤细胞亚群--bcr敏感和bcr不敏感之间有什么关系？我们假设几个模型：1.BCR不敏感群体起源于BCR敏感群体；2.两个肿瘤亚群中的每一个都起源于一个常见但罕见的肿瘤启动细胞，或3.BCR不敏感群体是更原始的细胞，最初产生主要的BCR敏感群体，但最终由于抗原刺激或对治疗的差异敏感性的负面选择力量而占主导地位。我们将通过将肿瘤细胞的两个亚群从个别病例中分离出来，并对各自的配对进行比较遗传分析来区分这些假说。我们将从每个亚群中克隆和测序VDJ区基因，并检测它们的V区体细胞突变模式。通过比较它们各自的进化路径，我们将推断出BCR敏感和BCR不敏感亚群之间的克隆关系。在第二种方法中，我们将比较两个肿瘤亚群之间DNA得失的全球模式，并确定每个亚群独特的变化。所有肿瘤细胞都应该与前体肿瘤细胞分享驱动DNA的得失；额外的得失应该揭示这两个亚群是如何相互进化的。最后，我们将在每种情况下寻找BCR不敏感的根本原因。利用下一代DNA测序技术，我们将对BCR信号通路的基因进行大规模的深度重新测序。我们希望在该途径的近端成员中发现突变。为了发现bcr敏感和bcr不敏感肿瘤细胞亚群之间的其他差异，我们将比较它们的基因表达谱。 公共卫生相关性：在这个项目中获得的知识可能导致基于我们最近发现的针对BCR不敏感的肿瘤亚群的滤泡性淋巴瘤的新疗法。这种肿瘤亚群随着时间的推移而扩大，并与对化疗的反应和患者总体存活率的下降有关。

DESCRIPTION (provided by applicant): Follicular lymphoma (FL) is generally an incurable disease. In each case the tumor is composed of a clonal population of B cells with a unique B cell antigen receptor (BCR). We have recently discovered that at the time of diagnosis, each FL tumor contains a subpopulation of tumor cells that has defective signaling through its B cell antigen receptor (1). The size of this BCR insensitive tumor subpopulation expands over time, and it predicts poor response to chemotherapy and a shorter overall survival. Thus, we pose the question "what is the relationship between the two subpopulations of tumor cells in follicular lymphoma- the BCR sensitive and the BCR insensitive?" We postulate several models:1. The BCR insensitive population arises from the BCR sensitive population, 2. Each of the two tumor subpopulations arises from a common but rare tumor-initiating cell, or 3. The BCR insensitive population is the more primitive cell that initially gives rise to the dominant BCR sensitive population but eventually dominates due to negative selective forces of antigenic stimulation or differential sensitivity to therapy. We will distinguish between these hypotheses by separating the two subpopulations of tumor cells from individual cases and by performing comparative genetic analyses on the respective pairs. We will clone and sequence the VDJ region genes from each subpopulation and examine their patterns of V region somatic mutations. By comparing their respective evolutionary paths we will infer the clonal relationships between the BCR sensitive and BCR insensitive subpopulations. In a second approach we will compare the global patterns of DNA gains and losses between the two tumor subpopulations and identify the changes unique to each. All tumor cells should share the driver DNA gains and losses with the progenitor tumor cell; additional gains and losses should reveal how the two subpopulations evolved in relation to each other. Finally, we will search for the root cause of BCR insensitivity in each case. Using next generation DNA sequencing technology, we will conduct large scale deep resequencing of genes of the BCR signaling pathway. We expect to find mutations in the proximal members of the pathway. In order to discover other differences between BCR sensitive and BCR insensitive tumor cell subsets we will compare their gene expression profiles. PUBLIC HEALTH RELEVANCE: The knowledge gained in this project may lead to new therapies for follicular lymphoma based on targeting a BCR insensitive tumor subpopulation that we have recently discovered. This tumor subpopulation expands over time and is correlated with response to chemotherapy and decreased overall survival of the patients.