Project 4 - Defining the Role of EBV in DLBCL Pathogenesis and Identification of Therapeutic Targets

PROJECT 4 – PROJECT SUMMARY/ABSTRACT Project 4. Defining the Role of EBV in DLBCL Pathogenesis and Identification of Therapeutic Targets Eric Johannsen, Project Leader; Shannon Kenney and Bill Sugden, Co-Leaders People living with HIV are at substantially increased risk of developing diffuse large B cell lymphoma (DLBCL), the most prevalent aggressive B cell lymphoma. DLBCL is not a single disease, but a group of histologically similar, but genetically distinct cancers. Defining DLBCL subtypes has shown distinct molecular pathways drive each subtype and has led to improvements in therapy. Although 5-10% of DLBCLs are EBV+, we lack an understanding of whether EBV associates with any of these genetic subtypes or is a distinct entity. We have discovered that about one-third of EBV+ DLBCLs correspond to the BCL6+Notch2 (BN2) DLBCL subtype and the remaining two-thirds fall outside of current DLBCL genetic classification. This project will: (1) fully define the genetic subtype(s) of DLBCL, including BN2, that are EBV associated; (2) determine the molecular mechanisms by which EBV latent genes interact with BN2 associated driver mutations to cause DLBCL; and (3) define the role of EBV in DLBCL and identify dependency factors in EBV+ DLBCL that can be targeted therapeutically.