# Stringent Latent Epstein-Barr Virus (EBV) Infection Collaborates with Cellular Gene Alterations to Induce EBV+ Lymphomas > **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $406,157 ## Abstract PROJECT SUMMARY/ABSTRACT Epstein-Barr virus is an important cause of human Burkitt lymphomas (BLs), Hodgkin lymphomas (HLs) and diffuse large B cell lymphomas (DLBCLs), particularly in AIDS patients. Although the EBV protein EBNA2 (which mimics Notch signaling) is required for EBV-induced transformation of B cells in vitro, cells that express EBNA2 have the “type III” form of viral latency, which is highly immunogenic. Thus, most EBV-infected human lymphomas, including BLs, HLs and DLBCLs, do not express EBNA2, even in AIDS patients. There is currently no in vivo or in vitro model available to study how EBV infection causes lymphomas in the absence of EBNA2 expression. BLs, which are largely driven by MYC translocations, have stringent type I latency (expressing only a single EBV protein, EBNA1) and currently the major role of EBV in BLs is thought to be prevention of MYC- induced apoptosis by the virally-encoded microRNAs. EBV+ HLs, which have type II latency, express only three viral proteins (EBNA1, LMP1 and LMP2A) and are thought to be driven by the LMP1 (a CD40 mimic) and LMP2A (a BCR mimic) proteins, in conjunction with cellular mutations that activate JAK/STAT signaling and a supportive CD4+ T cell-rich microenvironment. Here we propose to use a novel in vitro cell culture model, in combination with a cord blood-humanized (CBH) mouse model developed by our lab, to examine whether an EBNA2-deleted EBV mutant recently constructed by our lab (ΔEBNA2 EBV) can induce BL-like, HL-like or DLBCL-like lymphomas in vitro or in vivo when specific oncogenic pathways known to be induced in each type of tumor are activated, or tumors suppressor genes (TSGs) associated with these tumors are inactivated. Our promising preliminary results already suggest that over-expressing the MYC oncogene in B cells infected with the EBNA2- deleted EBV allows cells to form BL-like tumors with type I latency in NSG mice. In Aim 1, we will determine if ΔEBNA2 EBV cooperates with MYC, BCL6 and/or cyclin D3 over-expression to induce BL-like and/or germinal center (GC) type DLBCL-like lymphomas in NSG mice. In Aim 2, we will determine if ΔEBNA2 EBV cooperates with JAK/STAT activation or inhibition of plasma cell differentiation to cause HL-like lymphomas in NSG mice. In Aim 3, we will identify novel cellular gene mutations/alterations that cooperate with ΔEBNA2 EBV to induce BL- and/or HL-like or DLBCL-like lymphomas in NSG mice and define the mechanism(s) for this synergy. We hypothesize that EBNA2-deleted EBV will cooperate with cellular alterations commonly found in EBV+ BLs and/or HLs to induce BL-like and/or HL-like lymphomas in vivo (although the cellular mutations required to induce BL-like versus HL-like tumors will be different), and that our approach will also identify novel cellular gene alterations that cooperate with stringent EBV latency to cause AIDS-related lymphomas in humans. ## Key facts - **NIH application ID:** 10837753 - **Project number:** 5R01CA281379-02 - **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON - **Principal Investigator:** Shannon Celeste Kenney - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $406,157 - **Award type:** 5 - **Project period:** 2023-07-01 → 2028-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10837753 ## Citation > US National Institutes of Health, RePORTER application 10837753, Stringent Latent Epstein-Barr Virus (EBV) Infection Collaborates with Cellular Gene Alterations to Induce EBV+ Lymphomas (5R01CA281379-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10837753. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*