Epigenetic basis and therapeutic targeting of the unique lymphoma immunological niche - OVERALL: ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is an aggressiveand clinically heterogeneous malignancy derived from B-cells transiting the germinal center (GC) reaction. Indeed, the biological heterogeneity of DLBCL aligns with a continuum of developmental states within and subsequent to the GC reaction. The genetic hallmarks of DLBCL are somatic mutation in chromatin modifier and transcription factor genes and immune synapse signaling mediators. Examining mechanisms of action for these mutations has provided insights into discrete cell-intrinsic processes that are deregulated in DLBCL, but do not account for how these mutations function, when they occur together in the same lymphoma cells, how they shape the lymphoma microenvironment LME, how the LME influences lymphomas, and how critical host features such as age influence and define the nature of these lymphomas and their LME. DLBCLs are thus complex entities from the systems biology and immunological standpoint and a paradigm shift in our thinking about these tumors is necessary to arrive at a definitive understanding of disease pathogenesis and effective and precise therapeutic strategies. To address this challenge we have assembled a team of experts with distinct spheres of expertise, suites of cutting edge technologies and powerful and physiologically accurate model systems. They have worked together as a team to develop a compelling body of preliminary data supporting the conceptual framework of this proposal, and have developed critical resources such as shared genomics databases, primaryhuman PDX repositories, genetically engineered mouse models, computational pipelines and graphical user interfaces, and others. They will address the central hypotheses that i) chromatin is the key integrator, rheostat and executor of cell-intrinsic and cell- extrinsic pathways regulating key GC cell fate decisions downstream of immune synapse signaling, ii) DLBCLs reflect a continuum of malignant states with each tumor aligning with one or more points along GC B-cell epigenetic trajectories, iii) GCB and ABC DLBCLs are defined by crosstalk between their chromatin landscapes and other immune populations to shape the LME, iv) that these chromatin to LME effects vary in specific ways with mutation profiles and with aging age, and that v) rational targeting of DLBCLs must take into account and specifically antagonize these specific chromatin-immune synapse - LME scenarios to achieve long term tumor eradication.
