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

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.

Epstein-Barr Virus LMP1-Mediated Oncogenicity

“…The knockout of key pathway components promises to reveal why LMP1-induced canonical and noncanonical NF-B are each critical for LCL growth and survival, when they first become critical dependency factors, and how the crosstalk between LMP1-activated NF-B, MAPK, PI3 kinase, and interferon regulatory factor pathways sculpts target gene regulation. Similarly, LMP1 and LMP2A are typically coexpressed and colocalize in cell membranes, yet mechanisms by which they synergistically regulate a wide range of GC B-cell target genes are yet to be identified (69).…”

Extrafollicular activities: perspectives on HIV infection, germinal center-independent maturation pathways, and KSHV-mediated lymphoproliferation

“…Interestingly, recent transgenic mouse studies provide evidence that EBV proteins can also inhibit GC biology, particularly in the context of T cell defects. Expression of LMP1 and LMP2A in GC B lymphocytes under control of the AID promoter produced fatal lymphoproliferations only when both T and NK cells were depleted in the same animals [28]. In this model, which mimics EBV-HIV co-infection, there was a significant increase in the IgM plasmablast response, indicating that completion of the normal GC reaction was inhibited.…”

Current Progress in EBV-Associated B-Cell Lymphomas

“…Different from the application of humanized mouse model, a recent study reported establishment of a transgenic mouse model with conditional LMP1/2A coexpression in germinal center (GC) B cells [95]. In this mouse model, LMP1/2A showed very limited function in immunocompetent mice, while they promote B-cell lymphoproliferative diseases in the context of T-cell or NK-cell deficiency [95].…”

“…In this mouse model, LMP1/2A showed very limited function in immunocompetent mice, while they promote B-cell lymphoproliferative diseases in the context of T-cell or NK-cell deficiency [95]. …”