# Role of Epstein-Barr virus LMP2A protein in maintaining oncogenic IgM signaling in EBV+ B cell lymphomas

> **NIH NIH U01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $436,538

## Abstract

PROJECT SUMMARY
Epstein-Barr virus (EBV) causes a wide spectrum of lymphomas including Hodgkin, Burkitt, and diffuse large
cell lymphomas (DLBCL). The proportion of EBV+ lymphomas rises sharply as does morbidity and mortality in
HIV-infected persons despite combined antiretroviral therapy (cART), suggesting specific failure to control viral
driven lymphomas. However, the mechanistic processes contributing to EBV-driven lymphomagenesis remain
poorly understood. This proposal will investigate a conceptually novel hypothesis that the LMP2A viral
oncogene interacts with the B cell receptor (BCR), serving to maintain it in its growth promoting IgM isotype.
This hypothesis predicts that EBV transformed cells expressing LMP2A are dependent upon their constitutive
activation of cellular mediators of antigen-induced signaling, and thus will be susceptible to agents that target
this signaling cascade, whereas EBV-transformed cells that do not express LMP2A will be resistant to such
drugs. Our proposal stems from two exciting observations that we have made about lymphoblastoid cells
(LCLs) transformed by an EBV mutant that lacks LMP2A (∆LMP2A-EBV). First, we discovered that, unlike
normal LCLs, the growth of ∆LMP2A-LCLs is not dependent on mediators of antigen-induced signaling like
BLNK and BTK. Second, in contrast to normal LCLs, ∆LMP2A-LCLs fail to maintain the growth promoting IgM
form of the BCR and instead express the IgG-BCR. Since antigen signaling through IgG-BCR promotes
differentiation into plasma cells which secrete high levels of antibodies but have limited proliferative potential,
our central hypothesis is that LMP2A contributes to lymphomagenesis by facilitating outgrowth of EBV
transformed B lymphocytes expressing the growth promoting IgM-BCR. This proposal will analyze mechanistic
pathways and gene expression profiles in EBV-transformed LCLs and test lymphoma formation in humanized
mice in order to distinguish the direct contributions of LMP2A from those mediated by the IgM-BCR, and
assess the therapeutic vulnerability that arise from each. Specifically, we will (1) Investigate intersection of
LMP2A and BCR Ig isotype on B lymphocyte transformation, (2) Characterize impact of antigenic stimulation in
the presence or absence of LMP2A expression, and (3) Determine LMP2A-mediated susceptibility to
therapeutic inhibition of signaling molecules. Together these studies provide a framework for how LMP2A
interacts with the BCR to promote EBV transformation and provide new opportunities for therapeutic
intervention in EBV-associated lymphomas.

## Key facts

- **NIH application ID:** 10876339
- **Project number:** 5U01CA275247-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** ERIC C. JOHANNSEN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,538
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876339

## Citation

> US National Institutes of Health, RePORTER application 10876339, Role of Epstein-Barr virus LMP2A protein in maintaining oncogenic IgM signaling in EBV+ B cell lymphomas (5U01CA275247-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876339. Licensed CC0.

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