From pathogenesis to new therapeutic targets in Diffuse Large B cell Lymphoma

弥漫性大 B 细胞淋巴瘤从发病机制到新的治疗靶点

• 批准号: 9977975
• 负责人: Riccardo Dalla-Favera
• 金额: $ 96万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-04 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977975
• 关键词: Address; B-Lymphocytes; Biology; Cells; Clinical; Development; Gene Expression; Genes; Genetic; Genome; Goals; Human; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Mutation; Pathogenesis; Phenotype; Physiology; Preclinical Testing; Reaction; Regulation; Research Project Summaries; Role; Signal Pathway; Signaling Protein; Structure of germinal center of lymph node; Therapeutic Intervention; base; experience; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; new technology; new therapeutic target; programs; therapeutic candidate; tumor

Project Summary This research program is aimed at identifying new pathogenetic mechanisms in Diffuse Large B-Cell Lymphoma (DLBCL), the most common human lymphoma, as a mean to discover new targets for therapeutic intervention. DLBCL is a heterogeneous malignancy comprising genetically and clinically distinct phenotypes, which are derived from the malignant transformation of germinal center (GC) B cells at different stages of differentiation. Recent analysis of the DLBCL genome has identified a multitude of altered genes, most of which with unknown roles in normal GC physiology and lymphomagenesis. Thus, our program will address these issues by two main complementary approaches. First, we will use novel technologies allowing the analysis of signaling pathways and gene expression on a single cell basis from purified GC B cell subpopulations, as a mean to comprehensively identify the programs that are involved in GC development and potentially altered in DLBCL. Second, we will investigate the function and regulation of two GC “master regulators”, the activity of which is deregulated in DLBCL via mutational mechanisms as well as via alterations in “upstream” signaling pathways. The overall program is based on our long-standing experience in studying the biology of the GC reaction in relationship to the genetic mechanisms leading to its malignant transformation. We expect that the results of the above studies will identify new targets for therapy, which will be eventually tested pre-clinically in our portfolio of genetically defined mouse models of DLBCL.

项目摘要 该研究计划旨在确定弥漫性大B细胞中的新致病机制 淋巴瘤（DLBCL），最常见的人类淋巴瘤，是发现治疗新靶标的 干涉。 DLBCL是一种在遗传和临床上不同的表型完成的异质性恶性肿瘤， 这些是从不同阶段的生发中心（GC）B细胞的恶性转化得出的 分化。对DLBCL基因组的最新分析已经确定了许多改变的基因，大多数 在正常的GC生理学和淋​​巴作用中，其作用未知。那，我们的计划将解决 这些问题通过两种主要的完整方法。首先，我们将使用允许的新技术 从纯化的GC B细胞的单个细胞基础上分析信号通路和基因表达 亚群，作为全面确定与GC开发有关的计划的手段 在DLBCL中有可能改变。其次，我们将研究两个GC的功能和调节 调节器”，其活性在DLBCL中通过突变机制以及通过改变在DLBCL中进行了调节 在“上游”信号通路中。总体计划基于我们长期学习的经验 GC反应的生物学与遗传机制有关，导致其恶性 转型。我们希望以上研究的结果将确定治疗的新目标，这将 最终在我们的DLBCL遗传定义的小鼠模型的投资组合中进行预测试。