Submitted June 4, 2008
Accepted September 1, 2008
Epstein Barr virus latent membrane protein 2A exploits Notch1 to alter B cell identity in vivo
Leah J Anderson and Richard Longnecker*
Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
* Corresponding author; email: r-longnecker{at}northwestern.edu.
Expression of LMP2A during B cell development leads to global alterations in gene transcription similar to those seen in Hodgkin Reed Sternberg (HRS) cells of Hodgkin's Lymphoma (HL). Along with the consistent detection of LMP2A in EBV associated HL, this implicates a role for LMP2A in the pathogenesis of HL. We have shown that LMP2A constitutively activates the Notch1 pathway to auto-regulate the LMP2A promoter. To determine whether constitutive activation of the Notch pathway is important for LMP2A mediated alterations in B cell development in vivo, TgE-LMP2A transgenic mice were intercrossed with mice expressing loxP-flanked Notch1 genes and Cre recombinase. B cells from TgE Notch1lox/loxCD19+/Cre mice have an increase in IgM and CD43 and a decrease in CD5 expression in the bone marrow compared to TgE Notch1lox/lox mice, indicating the LMP2A signal for developmental aberrations is impaired in the absence of Notch1. Real-time RT-PCR analysis reveals that LMP2A requires the Notch1 pathway to alter levels of B cell specific transcription factors, E2A and EBF. Interestingly, Notch1 appears to be important for LMP2A mediated survival in low IL-7. We propose that LMP2A and the Notch1 pathway may cooperate to induce the alterations in B cell identity seen in HRS cells.
