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Abstract
Epstein–Barr virus (EBV) is associated with aggressive B cell lymphomas (BCLs). Latent membrane protein 1 (LMP1) of EBV is an oncogenic protein required for EBV B cell transformation. However, LMP1 is a weak oncogene in mice. Mice expressing Myc inserted 5’ of the Eμ enhancer (iMycEμ), mimicking the t(8;14) translocation of endemic Burkitt lymphoma, develop delayed onset BCLs. To investigate potential cooperation between LMP1 and oncogenic MYC, we produced mice expressing the LMP1 signaling domain via a hybrid CD40–LMP1 transgene (mCD40–LMP1), and the dysregulated MYC protein of aggressive EBV+ BCLs. mCD40-LMP1/iMycEμ mice trended toward earlier BCL onset. BCLs from mCD40–LMP1/iMycEμ mice expressed LMP1 and were transplantable into immunocompetent recipients. iMycEμ and mCD40–LMP1/iMycEμ mice developed BCLs with similar immunophenotypes. LMP1 signaling was intact in BCLs as shown by inducible interleukin-6. Additionally, LMP1 signaling to tumor cells induced the two isoforms of Pim1, a constitutively active prosurvival kinase implicated in lymphomagenesis.
Acknowledgements
This work was supported by RO1 CA099997 (G.A.B.) and RO1 CA151354 (S.J.) from the National Cancer Institute (NCI) and by a Carver Collaborative Pilot Grant to G.A.B. and S.J. from the University of Iowa. E.P.O. was supported by NIH T32 HL07344. This work was also supported, in part, by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The authors thank the University of Iowa Histopathology Laboratory for histology and immunohistochemistry assistance; the Holden Comprehensive Cancer Center Biostatistics core for statistics consultation; and members of the Janz and Bishop laboratories for helpful discussions.
Potential conflict of interest
Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.