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: 10224858
• 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/10224858
• 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.

项目概要 该研究项目旨在确定弥漫性大 B 细胞的新发病机制 淋巴瘤（DLBCL）是最常见的人类淋巴瘤，作为发现新治疗靶点的一种手段 干涉。 DLBCL 是一种异质性恶性肿瘤，具有遗传和临床不同的表型， 来源于生发中心（GC）B细胞在不同阶段的恶性转化。 差异化。最近对 DLBCL 基因组的分析发现了许多改变的基因，其中大部分 它在正常 GC 生理学和淋​​巴瘤发生中的作用尚不清楚。因此，我们的程序将解决 这些问题通过两种主要的互补方法解决。首先，我们将使用新技术 在纯化的 GC B 细胞的单细胞基础上分析信号通路和基因表达 亚群，作为全面识别 GC 开发和相关程序的一种手段 DLBCL 中可能发生改变。其次，我们将研究两个GC“master”的功能和调节 调节因子”，其活性在 DLBCL 中通过突变机制和改变而失调 在“上游”信号通路中。整个计划是基于我们长期的学习经验 GC反应的生物学与其恶性遗传机制的关系 转变。我们期望上述研究的结果将确定新的治疗靶点，这将 最终在我们的 DLBCL 基因定义小鼠模型组合中进行临床前测试。