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

项目摘要 这项研究计划旨在确定弥漫性大B细胞白血病的新发病机制。 淋巴瘤（DLBCL），最常见的人类淋巴瘤，作为一种手段，以发现新的目标， 干预DLBCL是一种异质性恶性肿瘤，包括遗传和临床上不同的表型， 其来源于不同阶段的生发中心（GC）B细胞的恶性转化， 分化最近对DLBCL基因组的分析已经确定了大量改变的基因，其中大部分是 其在正常GC生理学和淋巴瘤发生中的作用尚不清楚。因此，我们的计划将解决 这些问题通过两个主要的互补方法来解决。首先，我们将使用新技术， 从纯化的GC B细胞分析单细胞基础上的信号传导途径和基因表达 亚群，作为一种手段，全面识别涉及GC开发的程序， 在DLBCL中可能发生改变。其次，我们将探讨两个GC“主”的功能和调节 调节因子”，其活性在DLBCL中通过突变机制以及通过改变 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反应的生物学与导致其恶性的遗传机制的关系 转型我们希望上述研究的结果将确定新的治疗靶点， 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。

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.