Award
National Institute of Dental and Craniofacial Research 5R01DE032623-03
Exposing synthetic lethal vulnerabilities in EBV-positive AIDS-NHL through novel replication dependency factors
Recipient
University of Florida
Award Amount
$593,500.00
Ceiling
$593,500.00
Awarded
June 20, 2025
Identifier
5R01DE032623-03
This NIH-funded project investigates synthetic lethal vulnerabilities in EBV-positive AIDS-related non-Hodgkin lymphoma by studying novel replication dependency factors like ZC3H18, aiming to identify new therapeutic targets to improve treatment outcomes.
Description
Virus-associated lymphomas cause significant morbidity and mortality in HIV-infected individuals. Epstein-Barr virus (EBV) contributes to up to 90% of diffuse large B-cell lymphomas (DLBCL) and 40% of Burkitt lymphomas (BL). Despite improvements with antiretroviral therapy and chemotherapy, challenges remain, especially with virus-associated AIDS lymphomas. EBV-driven DNA replication, essential for lymphoma proliferation, is underexplored. EBV infection drives host DNA replication, which is crucial for viral latency and cancer cell proliferation but causes replication stress. This stress is a barrier to cancer, and EBV-cancer cells overcome it at replication forks. Using iPOND and mass spectrometry, ZC3H18 (ZC3) was identified as a critical replication dependency factor upregulated by EBV, facilitating host genome replication and lymphoma cell proliferation. Elevated ZC3 expression is observed in EBV+ DLBCL from AIDS patients. ZC3 interacts with MCM7, a core component of the helicase complex, indicating its role in proliferation. Targeting these factors may induce synthetic lethality, exploiting vulnerabilities in EBV+ lymphomas.