Genetic Basis of Signaling Heterogeneity in Human Follicular Lymphoma

人滤泡性淋巴瘤信号异质性的遗传基础

基本信息

批准号：
8232070
负责人：
RONALD LEVY
金额：
$ 49.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8232070
关键词：
Antigens B-Lymphocytes Biology Cell Separation Cells Clinical Clonal Evolution Clonal Expansion Collection Common Neoplasm Complement DNA DNA Resequencing DNA Sequence DNA analysis DNA copy number Data Diagnosis Disease Elements Etiology Follicular Lymphoma Gene Expression Genes Genetic Heavy-Chain Immunoglobulins Heterogeneity Human Individual Indolent Knowledge Lead Malignant - descriptor Malignant Neoplasms Methods Modeling Molecular Profiling Mutation Pathway interactions Patients Pattern Phenotype Phosphoric Monoester Hydrolases Phylogenetic Analysis Plant Roots Population Primary Neoplasm Receptor Signaling Receptors, Antigen, B-Cell Recurrence Sampling Signal Pathway Signal Transduction Signaling Pathway Gene Somatic Mutation Sorting - Cell Movement Specimen T-Lymphocyte Technology Testing Time Trees Variant base chemotherapy comparative genetic analysis genome-wide member neoplastic cell next generation novel primitive cell progenitor prognostic public health relevance response tumor variable region gene

项目摘要

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.

描述（由申请人提供）：滤泡性淋巴瘤（FL）通常是一种无法治愈的疾病。在每种情况下，肿瘤均由具有独特 B 细胞抗原受体 (BCR) 的 B 细胞克隆群组成。我们最近发现，在诊断时，每个 FL 肿瘤都含有一个肿瘤细胞亚群，该亚群通过其 B 细胞抗原受体的信号传导存在缺陷 (1)。这种 BCR 不敏感肿瘤亚群的规模随着时间的推移而扩大，它预示着化疗反应较差，总生存期较短。因此，我们提出了“滤泡性淋巴瘤中两个肿瘤细胞亚群——BCR 敏感和 BCR 不敏感”之间的关系是什么？我们假设几个模型：1。 BCR 不敏感群体源自 BCR 敏感群体，2. 两个肿瘤亚群中的每一个都源自常见但罕见的肿瘤起始细胞，或 3. BCR 不敏感群体是最初产生显性 BCR 的更原始细胞敏感人群，但由于抗原刺激的负选择力或对治疗的敏感性不同，最终占据主导地位。我们将通过从个体病例中分离肿瘤细胞的两个亚群并对各个对进行比较遗传分析来区分这些假设。我们将对每个亚群的 VDJ 区基因进行克隆和测序，并检查它们的 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 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 增加和丢失的总体模式，并确定每个亚群独特的变化。所有肿瘤细胞都应与祖肿瘤细胞共享驱动DNA的获得和丢失；额外的收益和损失应该揭示这两个亚群体之间的相互关系是如何演变的。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深度重测序。我们期望在该通路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：在该项目中获得的知识可能会带来基于我们最近发现的 BCR 不敏感肿瘤亚群的滤泡性淋巴瘤的新疗法。该肿瘤亚群随着时间的推移而扩大，并与化疗反应和患者总生存率降低相关。