Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 25, Pages 14421-14432Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1921139117
Keywords
Epstein-Barr virus; LMP1; EBNA; B cell lymphomagenesis; plasma cell differentiation
Categories
Funding
- European Research Council [268921]
- Helmholtz Alliance Preclinical Comprehensive Cancer Center of the Helmholtz Association's Initiative and Networking Fund [HA-305]
- Helmholtz-Gemeinschaft, Zukunftsthema Immunology and Inflammation [ZT-0027]
- Medical Research Council, UK
- MRC [MR/M008584/1, MC_PC_17230] Funding Source: UKRI
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Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.
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