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

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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.