Author:
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
Abstract
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.
Funder
HHS | NIH | National Cancer Institute
HHS | NIH | National Institute of Allergy and Infectious Diseases
Japan Society for the Promotion of Science
Leukemia and Lymphoma Society
Publisher
Proceedings of the National Academy of Sciences
Cited by
46 articles.
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