Mouse model of Epstein–Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 18; pp. 4751 - 4756
• Main Authors: Minamitani, Takeharu, Ma, Yijie, Zhou, Hufeng, Kida, Hiroshi, Tsai, Chao-Yuan, Obana, Masanori, Okuzaki, Daisuke, Fujio, Yasushi, Kumanogoh, Atsushi, Zhao, Bo, Kikutani, Hitoshi, Kieff, Elliott, Gewurz, Benjamin E., Yasui, Teruhito
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02-05-2017
• Series: From the Cover
• Subjects: B-cell lymphoma; B-cell receptor; Biological Sciences; CD30 antigen; CD40 antigen; Cell differentiation; Cell survival; Chemokines; Damage detection; Differentiation (biology); Epstein-Barr virus; Gene expression; Gene regulation; Gene sequencing; Germinal centers; Herpes viruses; Hodgkin's lymphoma; Immunoproliferative diseases; Immunosuppression; Inflammation; Latent membrane protein 1; LMP2A protein; Lymphocytes B; Lymphoma; Markers; Membrane proteins; Membranes; Proteins; Ribonucleic acid; RNA; Rodents; Viruses; LMP1; plasmablast; posttransplant lymphoproliferative disorder; LMP2A; Epstein–Barr virus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1701836114

Epstein–Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases.