# Metabolic Network Remodeling in Epstein-Barr Virus Lymphomagenesis

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $447,500

## Abstract

Abstract
 Epstein-Barr virus (EBV), the first identified human tumor virus, transforms resting B-cells into
rapidly growing lymphoblasts. EBV-driven lymphomas cause significant disease in patients with
primary or acquired immunodeficiency, including post-transplantation, with HIV co-infection or
with age-related immune-senescence. EBV transforms human B-cells through a program that
involves at least three early stages. First, EBV causes major B-cell anabolic remodeling, prior to
cell cycle entry. Second, EBV then drives rapid Burkitt-lymphoma (BL) like B-cell growth,
triggering cell division every 8-12 hours. Finally, EBV LMP1 and 2A oncoprotein expression
cause a transition to lymphoblastoid cell line (LCL)-like growth, where cells divide daily and
complete the immortalization program. To achieve this remarkable transition, EBV subverts key
host metabolic networks to provide energy, biosynthetic building blocks and protection from
reactive oxygen species. Yet, comprehensive approaches have not been used to identify key
EBV-targeted mitochondrial metabolic pathways that underlie EBV-mediated B-cell growth
transformation. We therefore used multiplexed mass spectrometry to create a temporal
proteomic map of EBV-mediated primary human B-cell transformation, and used genome-wide
CRISPR screens to identify EBV-induced B-cell dependency factors. These approaches
identified a central role for EBV-induced mitochondrial one-carbon (1C) metabolism, an
embryonic program that enables rapid cell growth but which is shut off in many adult tissues.
Our preliminary data indicates that EBV oncoproteins induce 1C metabolism, including in a
mouse model of lymphoproliferative disease. Our central hypothesis is that EBV-induced
mitochondrial one-carbon metabolism has critical but distinct roles in each stage of EBV-
mediated B-cell growth transformation. Our Specific Aims are therefore to: 1) Identify the role
of EBV-induced 1C metabolism in primary B-cell remodeling; (2) Identify the role of one-carbon
metabolism in support of rapid Burkitt-like growth; (3) Identify mitochondrial 1C roles in LCL-like
cell redox defense. Collectively, these studies are expected to identify how EBV subverts a key
embryonic mitochondrial pathway to enable potent growth transformation. 1C metabolism has
not been studied in EBV pathogenesis, but is closely related to host enzyme targets blocked by
antifolate lymphoma therapies. Our studies may therefore support strategies to develop rational
therapeutic regimens to halt EBV-associated malignancies.

## Key facts

- **NIH application ID:** 10111452
- **Project number:** 5R01AI137337-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Benjamin Elison Gewurz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,500
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111452

## Citation

> US National Institutes of Health, RePORTER application 10111452, Metabolic Network Remodeling in Epstein-Barr Virus Lymphomagenesis (5R01AI137337-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10111452. Licensed CC0.

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