# Defining mechanisms of gammaherpesvirus-driven genomic instability in B cells

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2024 · $59,432

## Abstract

PROJECT SUMMARY
Gammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerous
cancers. During chronic infection, GHVs express viral gene products that stimulate host-cell proliferation and
differentiation, processes thought to facilitate long-term latent persistence and contribute to tumorigenesis.
However, GHVs are not acutely transforming, and cancer is rare given the high incidence of infection among
adult humans, estimated at more than 95% for Epstein-Barr virus (EBV). This suggests that host cells are
equipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization. In work performed
during the previous funding period, we identified the tumor suppressor p53 as a protein that is activated during
the establishment of GHV latent infection. p53 is frequently considered a “guardian of the genome”, working
downstream of multiple mutagenic pathways to halt cell-cycle progression, stimulate DNA repair, or promote
apoptosis. p53 is frequently mutated in human cancers, including endemic Burkitt lymphoma, an EBV-associated
lymphoma that is characterized by a chromosomal translocation between the immunoglobulin heavy-chain
promoter and cellular proto-oncogene c-myc. It is hypothesized that EBV synergizes with malaria, to promote
the survival of cells that harbor IgH/c-myc translocations. Using murine gammaherpesvirus 68 (MHV68) infection
of mice as a small animal model to enable a multi-system analysis GHV pathogenesis, we demonstrated that
p53 limits cellular proliferation, especially of germinal center (GC) cells. We also found that p53 inhibits IgH/c-
myc translocations in B cells of infected mice, an event that correlates with enhanced B cell lymphoma
development in p53-deficient mice infected with MHV68. Moreover, we provide preliminary data indicating that
co-infection of mice with MHV68 and a murine malaria parasite also promotes IgH/c-myc translocations.
Experiments proposed in this competing renewal will build on our previous progress, harnessing the powerful
mouse and MHV68 genetic systems, to (i) define viral genes and molecular pathways that promote genomic
instability and lymphoma development, (ii) identify viral and host-factor dependencies in GHV-driven lymphomas,
and (iii) determine the mechanisms through which MHV68 and murine Plasmodium parasites facilitate
chromosomal translocations. In addition to providing a better understanding of how GHVs cause disease, we
anticipate that results of this work will inform new therapeutic approaches that target lymphoma dependencies
and reduce the mutagenic potential of GHVs and related co-infections.

## Key facts

- **NIH application ID:** 10977288
- **Project number:** 3R01CA167065-08S1
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** James Craig Forrest
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $59,432
- **Award type:** 3
- **Project period:** 2014-04-04 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977288

## Citation

> US National Institutes of Health, RePORTER application 10977288, Defining mechanisms of gammaherpesvirus-driven genomic instability in B cells (3R01CA167065-08S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10977288. Licensed CC0.

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