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A 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 lymphomas. EB-driven lymphoproliferative disease complicates up to 20% of transplants, and EBV is a major cause of human immunodeficieciency virus associated lymphomas. Despite successful antiretroviral therapy, the incidence of EBV-associated Hodgkin lymphoma continues to increase in HIV+ individuals. To gain insights into EBV membrane oncoprotein effects on B-cell growth, survival and pathogenesis in vivo, we generated transgenic mouse models, in which knock-in mice transgenically express control GFP or EBV latent membrane proteins (LMP) 1 and 2A under the control of the AICDA promoter. Upon T and NK-cell depletion by antibody cocktail, LMP1 and 2A co-expression drove explosive growth of plasmablastic lymphoma-like cells, which proliferated in the spleen, caused severe end-organ damage and death. RNAseq profiling identified genome-wide LMP1 and 2A effects on B-cell gene expression, including dramatic effects on chemokine and cytokine production. While cells exhibited plasmablast features, LMP1 and 2A co-expression also induced mixed hematopoietic lineage markers, a well described but incompletely understood feature of Hodgkin lymphoma. Collectively, our results identify synergistic effects of EBV membrane oncoprotein expression, and highlight their role in lymphoproliferative diseases of immunocompromised hosts. Overall design: B220 positive B splenocytes were isolated from GFP and LMP1/2a transgenic mice, which are T/NK cell depleted by antibody cocktails, and subjected to RNA-seq analysis to compare the transcriptomic changes in LMP1/2a transgenic mice compared to GFP transgenic mice. Two mice from each transgenic group were used.

INSTRUMENT(S): Illumina NextSeq 500 (Mus musculus)

SUBMITTER: Benjamin Gewurz  

PROVIDER: GSE93827 | GEO | 2017-03-16



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

Minamitani Takeharu T   Ma Yijie Y   Zhou Hufeng H   Kida Hiroshi H   Tsai Chao-Yuan CY   Obana Masanori M   Okuzaki Daisuke D   Fujio Yasushi Y   Kumanogoh Atsushi A   Zhao Bo B   Kikutani Hitoshi H   Kieff Elliott E   Gewurz Benjamin E BE   Yasui Teruhito T  

Proceedings of the National Academy of Sciences of the United States of America 20170328 18

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 an  ...[more]

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