Large-scale functional interrogation of evolutionary forces in pre-germinal center B cell lymphoma development

对生发前中心 B 细胞淋巴瘤发展中进化力量的大规模功能询问

• 批准号: 468687596
• 负责人: Professor Dr. Roland Rad
• 金额: --
• 依托单位: Institut für Molekulare Onkologie und Funktionelle Genomik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/468687596?language=en
• 关键词: Large; scale; functional; interrogation; evolutionary

Mantle cell lymphoma (MCL) is an aggressive malignancy, characterized by Cyclin D1 overexpression through a chromosomal translocation acquired during early B cell development. Genome sequencing has given important insights into the mutational landscapes of MCL, but also revealed many layers of unexplored complexity, which is far from being understood. Gene dysregulation by non-genetic mechanisms, including epigenetic and transcriptional changes, is widespread, and discriminating the relevant drivers is challenging. Identifying the key regulatory nodes, positioning them in pathways, networks and processes, understanding genetic interactions and pathway rewiring, dissecting the extensive context-dependency of signaling outputs and understanding cell/cell communication in the tumor microenvironment are only some of the major unresolved challenges. Building on mouse models, genetic tools, methodologies and data resources developed by us, we propose to address these challenges at different levels. In AIM-1 and 2 we will perform genome wide screens and comprehensive large-scale surveys to characterize cell-intrinsic and extrinsic processes underlying lymphoma evolution. By combining in vivo functional screening with high-resolution chromatin profiling and super-enhancer mapping, we aim to discover core cell-intrinsic regulatory circuitries driving different stages of tumor evolution in mice (AIM-1). We will also characterize the composition and architecture of the lymphoma microenvironment and monitor its changes longitudinally during lymphoma initiation and progression (AIM-2). Single cell sequencing and multispectral imaging will aid systematic surveys for cellular and molecular players involved in cell/cell communication within the MCL niche. In AIM-3 we will functionally characterize key discoveries emanating from aim-1/2. One focus is triggered by our recent work on CD40 activation, a hallmark event in MCL, which discovered an unexpected role of IL9/IL9R mediated cell/cell communication in lymphoma pathogenesis. Our data suggest consecutive feed-forward loops involving multiple molecular and cellular constituents. We will functionally interrogate this model in mice by characterizing the involved cell types, genes, signaling pathways, as well as organismal phenotypes related to their perturbation.The systematic discovery and mechanistic characterization of key regulatory nodes, processes and dependencies in MCL evolution is promising to inform precision oncology efforts in MCL. Moreover, the rich data resource created here will drive hypothesis generation and downstream functional studies far beyond the framework of this proposal.

地幔细胞淋巴瘤（MCL）是一种侵略性恶性肿瘤，其特征是Cyclin D1通过在早期B细胞发育期间获得的染色体易位过表达。基因组测序对MCL的突变景观提供了重要的见解，但也揭示了许多未开发的复杂性层，这远非被理解。非遗传机制（包括表观遗传和转录变化）通过非遗传机制的基因失调是广泛的，并且区分相关驱动因素是具有挑战性的。确定关键的调节节点，将它们定位在途径，网络和过程中，了解遗传相互作用和路线重新布线，解剖信号输出的广泛上下文依赖性以及了解肿瘤微环境中的细胞/细胞通信只是一些主要未解决的尚未解决的挑战。在我们开发的鼠标模型，遗传工具，方法和数据资源的基础上，我们建议在不同层面上解决这些挑战。在AIM-1和2中，我们将执行基因组宽筛选和全面的大规模调查，以表征淋巴瘤进化的细胞中性和外在过程。通过将体内功能筛选与高分辨率染色质分析和超增强剂映射相结合，我们旨在发现小鼠肿瘤进化的不同阶段的核心细胞内部调节循环（AIM-1）。我们还将表征淋巴瘤微环境的组成和结构，并在淋巴瘤开始和进展过程中纵向监测其变化（AIM-2）。单细胞测序和多光谱成像将有助于系统的调查，以实现与MCL生态裂细胞/细胞通信有关的细胞和分子参与者的系统调查。在AIM-3中，我们将在功能上表征AIM-1/2发出的关键发现。我们最近在MCL中的标志性事件CD40激活的工作引起了一个焦点，该活动发现IL9/IL9R介导的细胞/细胞通信在淋巴瘤发病机理中的意外作用。我们的数据表明，涉及多个分子和细胞成分的连续进馈回路。我们将通过表征涉及的细胞类型，基因，信号通路以及与其扰动相关的有机体表型来在功能上询问小鼠中的模型。系统的发现和机械表征关键调节节点，过程和依赖性的MCL进化中的依赖性是在MCL中的精确侵袭性工作。此外，这里创建的丰富数据资源将推动假设产生和下游功能研究远远超出了该提案的框架。