# Epstein-Barr virus LMP1 mediated oncogenicity

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $409,463

## Abstract

Abstract
 Gamma-herpesvirus-driven lymphoproliferative disorders cause significant mortality in HIV+
populations. Despite highly active antiretroviral therapy, HIV+ individuals remain at elevated risk
for Epstein-Barr virus (EBV)-associated B-cell cancers. EBV is identified in >40% of
immunoblastic diffuse large B-cell lymphomas and nearly 100% of Hodgkin lymphoma and
primary central nervous system lymphomas in HIV+ individuals. EBV transforms human B-cells
into lymphoblastoid cell lines (LCL), a major model of EBV-driven immunoblastic lymphomas of
immunosuppressed hosts. Yet, key EBV-induced host dependency factors remain to be
elucidated. We therefore used systematic approaches to gain insights into key EBV oncoprotein
targets. We used: 1) Genome-wide CRISPR screens to identify host dependency factors
downstream of EBV oncoproteins; 2) Multiplexed mass spectrometry to create a proteomic map
of EBV-mediated B-cell transformation; and 3) ChIP-seq to identify EBV oncoprotein host
genomic targets, which found the first viral super-enhancers (SE), comprised of 5 LMP1-
activated NF-kB and 4 EBV nuclear antigen subunits. These converged on the transcription
factors BATF, IRF4 and IRF2 as key LMP1-targeted host dependency factors. Our preliminary
studies indicate that BATF/IRF4 and IRF2 complexes have key dependency factor roles in EBV
oncoprotein-driven MYC expression, necessary for LCL growth and survival. We propose to
define how the interplay between viral oncoprotein superenhancers, BATF/IRF4 and IRF2
complexes drive MYC expression in lymphoblastoid B-cells. Our Specific Aims are to (1)
Identify how EBV oncoproteins activate dependency factor BATF/IRF4 complexes to induce
MYC; (2) Identify key BATF/IRF4 roles in EBV oncoprotein-induced MYC induction in
lymphoblastoid B-cells; and (3) Identify how the viral SE-driven dependency factor IRF2 is
necessary to support lymphoblastoid cell MYC expression. These studies specifically address
PA-16-426 by advancing understanding of development, progression and treatment of
malignancies observed in individuals with underlying HIV infection. The proposed studies are
expected to contribute to understanding of how EBV oncoproteins and key genetically-defined
downstream host dependency factors reprogram lymphoblastoid cell MYC expression. EBV
oncoproteins may not be druggable, but SE and IRF4 are increasingly therapeutic targets. Since
viral oncoprotein-induced MYC expression is critical for EBV-transformed B-cell growth, the
longterm goal of these studies is to support rational approaches to restrain viral oncogene
subversion of MYC.

## Key facts

- **NIH application ID:** 10020965
- **Project number:** 5R01CA228700-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Benjamin Elison Gewurz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,463
- **Award type:** 5
- **Project period:** 2019-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020965

## Citation

> US National Institutes of Health, RePORTER application 10020965, Epstein-Barr virus LMP1 mediated oncogenicity (5R01CA228700-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020965. Licensed CC0.

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