Functional interplay of Epstein-Barr virus oncoproteins in a mouse model of B cell lymphomagenesis.

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Yasuda, Tomoharu 
Wirtz, Tristan 

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.

B cell lymphomagenesis, EBNA, Epstein-Barr virus, LMP1, plasma cell differentiation, Animals, Cell Differentiation, Cell Line, Tumor, Cell Transformation, Viral, DNA-Binding Proteins, Disease Models, Animal, Epstein-Barr Virus Infections, Epstein-Barr Virus Nuclear Antigens, Fibroblasts, Herpesvirus 4, Human, Humans, Lymphoma, B-Cell, Mice, Mice, Knockout, Plasma Cells, Primary Cell Culture, Trans-Activators, Viral Matrix Proteins, Viral Proteins
Journal Title
Proc Natl Acad Sci U S A
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Proceedings of the National Academy of Sciences
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Medical Research Council (MR/M008584/1)
Medical Research Council (MC_PC_12009)
Medical Research Council (MC_PC_17230)