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

项目摘要 本研究旨在确定弥漫性大B细胞新的发病机制 淋巴瘤(DLBCL)，人类最常见的淋巴瘤，作为发现新的治疗靶点的手段 干预。DLBCL是一种包括遗传和临床不同表型的异质性恶性肿瘤， 它们起源于生发中心(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，其中大多数 在正常的GC生理和淋巴肿大中的作用尚不清楚。因此，我们的计划将解决 这些问题可以通过两种主要的互补办法加以解决。首先，我们将使用新技术，使 纯化的GC-B细胞单细胞信号通路及基因表达分析 亚群，作为一种手段，全面确定参与GC发展和 在DLBCL中可能发生了更改。其次，我们将研究两个GC“大师”的功能和调控 调节器“，其活动在DLBCL中通过突变机制以及通过改变来解除管制 在“上游”信号通路中。整个计划是基于我们长期学习的经验 GC反应的生物学与致癌遗传机制的关系 转型。我们预计上述研究的结果将确定新的治疗目标，这将 最终在我们的DLBCL基因定义的小鼠模型组合中进行临床前测试。

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.