PROJECT 3: SUMMARY/ABSTRACT This project focus in the biology of diffuse large B-cell lymphoma (DLBCL) in older individuals (i.e., patients 75 years or older). Based on findings in national cohorts from our group and others, DLBCL in older patients is associated with comparatively worse outcomes even when accounting for treatment intensity and lymphoma subtype. Our preliminary data suggest that intrinsic biological differences in DLBCL in older patients may account for their poor response to chemoimmunotherapy. For example, we found that DLBCL in older patients associates with higher proportion of activated B-cell-like (ABC) DLBCLs and higher number of inflammatory cells in the lymphoma microenvironment. The reasons for these differences are not yet fully elucidated. Since aging, even healthy aging, is associated with epigenetic alterations across tissues and epigenetics influences the physiology and pathology of B cells, we hypothesize that some of the biological differences in DLBCL in older patients is driven by epigenetic alterations of aging (EAA). In this project, we will determine whether EAA in B cells predispose them to lymphomagenesis driven by MYD88 mutations, a frequent event in ABC-DLBCLs. Other projects in this P01 are exploring the mechanisms by which MYD88 and other immune synapse mutations activating the BCR pathway, modify the epigenetic landscape of B cells to drive lymphomagenesis. Using “fertile soil” concept, we proposed that EAAs make B cells prone to malignant transformation by immune synapse mutations. Concomitantly, we propose that EAA affecting immune and stromal cells that populate the microenvironment are prone to acquire inflammatory phenotypes that contribute to lymphoma progression. Other projects in this P01 are exploring the epigenetic mechanisms that allow B cells in physiological and pathological contexts to receive proliferation and survival signals from immune microenvironment cells. We plan to test our central hypothesis and accomplish the objective of this project by pursuing these specific aims to: (1) Elucidate EAAs that reprogram GC B cells and enable the activity of ABC-DLBCL oncogenes; (2) Elucidate mechanisms in the aging microenvironment that are permissive for lymphomagenesis; and (3) Develop therapeutic approaches that target the aging phenotype. Thus, our project will provide the scientific rationale to design biologically driven chemotherapy-free combinatorial treatments for older DLBCL patients. Overall, our project is integral to the ideas explored in this P01 adding a biologically and clinically relevant perspective from the aging standpoint, for what we anticipate will be an unprecedented understanding of the complex epigenetic mechanisms that regulate the immune synapse in DLBCL patients.