RESEARCH SUMMARY Increased understanding of the molecular mechanisms underlying non-Hodgkin's lymphoma (NHL) has opened the door for targeted therapy in aggressive diffuse large B-cell lymphoma (DLBCL) and indolent marginal zone lymphomas (MZLs). Based on distinct gene expression profiles, DLBCLs are classified into B cell receptor signaling-driven activated B cell-like (ABC) subtypes and epigenetics-driven germinal center B cell-like (GCB) subtypes but have widely divergent outcomes: ABC-DLBCL is the most chemo-resistant subtype to the frontline therapy R-CHOP, with 40% of patients experiencing no response or relapse. Co-I Dr. Jean Koff's collaborative research showed that genetic alterations interact with clinical factors to impact overall survival (OS) in DLBCL. Our group has systematically examined disparities in lymphoma outcomes and identified African-American (AA) patients as a poor-risk population in DLBCL, with diagnosis age 10 years younger than other racial groups. In the Surveillance, Epidemiology and End Results (SEER) dataset and other analyses, we found that AA-DLBCL patients experienced inferior 5-year OS compared to non-Hispanic whites (38% vs 46). Dr. Koff performed the first-ever characterization of genetic alterations among AA-DLBCL patients and demonstrated distinct mutation patterns across DLBCL arising in discrete ancestry groups. While some of the most frequent genetic mutations in AA-DLBCL are related to chromatin and epigenetics, few studies have investigated racial disparities in patients with aggressive ABC DLBCLs and indolent MZLs. In a large, population-based analysis of patients with indolent NHL in the US, data presented at American Society for Hematology reported inferior survival in racial and ethnic minorities over the past two decades, with AAs among the 2nd highest mortality group. The mechanisms that determine this racial inequality are unknown, but may lie in the particular spectrum of mutations that act in concert with intricate survival signals imparted by the lymph node tumor microenvironment (Ly-TME). Investigations into the molecular factors that may contribute to racial disparities in lymphoma have been limited by the under- representation of AA patients, even in very large lymphoma biorepositories. The long-term goal of this R01 is to understand the racial disparities in lymphoma outcomes through complex interactions between Ly-TME and DLBCL and MZL cells in AA patient samples, recapitulate AA-DLBCL and AA-MZL Ly-TME in a tunable hydrogel platform, and determine the role of Ly-TME on tumor survival, signaling, and response to BCR pathway inhibitors. The R01 is innovative because it investigates mechanisms underlying racial disparity AA-Ly-TME and develops AA-DLBCL organoids. The proposed work is significant because it will examine how AA-Ly-TME differs from that of white patients and determine its impact on BCR signaling and BTKi.