A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma

Bieging, Kathryn T.; Fish, Kamonwan; Bondada, Subbarao; Longnecker, Richard

doi:10.1182/blood-2011-02-338434

Cited by 14 publications

(12 citation statements)

References 44 publications

(92 reference statements)

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“…LMP2A is also known to be expressed in the GC B cells of healthy virus carriers, in which cells it has been assumed, based on previous studies in transgenic mouse models and in lymphoblastoid cell lines, to provide a surrogate BCR signal . In the present study we have shown that LMP2A expression does indeed recapitulate many of the transcriptional changes induced by BCR ligation in primary human germinal centre B cells.…”

Section: Discussionsupporting

confidence: 68%

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Suppression of the LMP2A target gene, EGR‐1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle

Vockerodt

Wei

Nagy

et al. 2013

The Journal of Pathology

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Hodgkin's lymphoma is unusual among B cell lymphomas, in so far as the malignant Hodgkin/Reed-Sternberg (HRS) cells lack a functional B cell receptor (BCR), as well as many of the required downstream signalling components. In Epstein-Barr virus (EBV)-positive cases of Hodgkin's lymphoma, HRS cells express the viral latent membrane proteins (LMP)-1 and -2A. LMP2A is thought to contribute to the pathogenesis of Hodgkin's lymphoma by providing a surrogate BCR-like survival signal. However, LMP2A has also been shown to induce the virus-replicative cycle in B cells, an event presumably incompatible with lymphomagenesis. In an attempt to resolve this apparent paradox, we compared the transcriptional changes observed in primary HRS cells with those induced by LMP2A and by BCR activation in primary human germinal centre (GC) B cells, the presumed progenitors of HRS cells. We found a subset of genes that were up-regulated by both LMP2A expression and BCR activation but which were down-regulated in primary HRS cells. These genes included EGR1, an immediate-early gene that is required for BCR-induced entry to the virus-replicative cycle. We present data supporting a model for the pathogenesis of EBV-positive Hodgkin's lymphoma in which LMP2A-expressing HRS cells lacking BCR signalling functions cannot induce EGR1 and are consequently protected from entry to the virus lytic cycle. The primary microarray data are available from GEO (http://www.ncbi.nlm.nih.gov/geo/) under series Accession No 46143.

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Section: Discussionsupporting

confidence: 68%

“…BZLF1 has also been shown to bind to the EGR1 promoter and activate its expression . Recently, Egr‐1 was reported to be up‐regulated in an LMP2A‐expressing mouse model of Burkitt's lymphoma, suggesting that Egr‐1 might also be regulated by LMP2A .…”

Section: Introductionmentioning

confidence: 99%

Suppression of the LMP2A target gene, EGR‐1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle

Vockerodt

Wei

Nagy

et al. 2013

The Journal of Pathology

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“…Both lines express the transgene under the control of the IgH promoter and enhancer region, rendering transgene expression B cell-specific. The well-described LMP2A Tg6 line has no gross defect in B cell numbers, B cell development, or BCR expression [31] , [32] , [43] . In LMP1 lineage 3 mice, modest alterations have been described in B cell maturation in the periphery, as well as the ablation of germinal center (GC) formation in response to antigen [16] .…”

Section: Resultsmentioning

confidence: 99%

Epstein-Barr Virus LMP2A Reduces Hyperactivation Induced by LMP1 to Restore Normal B Cell Phenotype in Transgenic Mice

et al. 2012

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Epstein-Barr virus (EBV) latently infects most of the human population and is strongly associated with lymphoproliferative disorders. EBV encodes several latency proteins affecting B cell proliferation and survival, including latent membrane protein 2A (LMP2A) and the EBV oncoprotein LMP1. LMP1 and LMP2A signaling mimics CD40 and BCR signaling, respectively, and has been proposed to alter B cell functions including the ability of latently-infected B cells to access and transit the germinal center. In addition, several studies suggested a role for LMP2A modulation of LMP1 signaling in cell lines by alteration of TRAFs, signaling molecules used by LMP1. In this study, we investigated whether LMP1 and LMP2A co-expression in a transgenic mouse model alters B cell maturation and the response to antigen, and whether LMP2A modulates LMP1 function. Naïve LMP1/2A mice had similar lymphocyte populations and antibody production by flow cytometry and ELISA compared to controls. In the response to antigen, LMP2A expression in LMP1/2A animals rescued the impairment in germinal center generation promoted by LMP1. LMP1/2A animals produced high-affinity, class-switched antibody and plasma cells at levels similar to controls. In vitro, LMP1 upregulated activation markers and promoted B cell hyperproliferation, and co-expression of LMP2A restored a wild-type phenotype. By RT-PCR and immunoblot, LMP1 B cells demonstrated TRAF2 levels four-fold higher than non-transgenic controls, and co-expression of LMP2A restored TRAF2 levels to wild-type levels. No difference in TRAF3 levels was detected. While modulation of other TRAF family members remains to be assessed, normalization of the LMP1-induced B cell phenotype through LMP2A modulation of TRAF2 may be a pathway by which LMP2A controls B cell function. These findings identify an advance in the understanding of how Epstein-Barr virus can access the germinal center in vivo, a site critical for both the genesis of immunological memory and of virus-associated tumors.

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“…Two others (EPCAM epithelial cell specific trans-membrane glycoprotein, and PPARG chemokine), as well as REG4, are being explored for targeted cancer therapy [64-66]. The last of the seven, BBC3 (also called p53 up-regulated modulator of apoptosis, or PUMA) is reportedly upregulated by EBV LMP2A and reigned in by EBV miR-BART5 in cell line models [67,68], suggesting that this BCL2 family member is tightly regulated by the virus.…”

Section: Discussionmentioning

confidence: 99%

Epstein-barr virus infected gastric adenocarcinoma expresses latent and lytic viral transcripts and has a distinct human gene expression profile

Tang

Morgan

Meyers³

et al. 2012

Infect Agents Cancer

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BackgroundEBV DNA is found within the malignant cells of 10% of gastric cancers. Modern molecular technology facilitates identification of virus-related biochemical effects that could assist in early diagnosis and disease management.MethodsIn this study, RNA expression profiling was performed on 326 macrodissected paraffin-embedded tissues including 204 cancers and, when available, adjacent non-malignant mucosa. Nanostring nCounter probes targeted 96 RNAs (20 viral, 73 human, and 3 spiked RNAs).ResultsIn 182 tissues with adequate housekeeper RNAs, distinct profiles were found in infected versus uninfected cancers, and in malignant versus adjacent benign mucosa. EBV-infected gastric cancers expressed nearly all of the 18 latent and lytic EBV RNAs in the test panel. Levels of EBER1 and EBER2 RNA were highest and were proportional to the quantity of EBV genomes as measured by Q-PCR. Among protein coding EBV RNAs, EBNA1 from the Q promoter and BRLF1 were highly expressed while EBNA2 levels were low positive in only 6/14 infected cancers. Concomitant upregulation of cellular factors implies that virus is not an innocent bystander but rather is linked to NFKB signaling (FCER2, TRAF1) and immune response (TNFSF9, CXCL11, IFITM1, FCRL3, MS4A1 and PLUNC), with PPARG expression implicating altered cellular metabolism. Compared to adjacent non-malignant mucosa, gastric cancers consistently expressed INHBA, SPP1, THY1, SERPINH1, CXCL1, FSCN1, PTGS2 (COX2), BBC3, ICAM1, TNFSF9, SULF1, SLC2A1, TYMS, three collagens, the cell proliferation markers MYC and PCNA, and EBV BLLF1 while they lacked CDH1 (E-cadherin), CLDN18, PTEN, SDC1 (CD138), GAST (gastrin) and its downstream effector CHGA (chromogranin). Compared to lymphoepithelioma-like carcinoma of the uterine cervix, gastric cancers expressed CLDN18, EPCAM, REG4, BBC3, OLFM4, PPARG, and CDH17 while they had diminished levels of IFITM1 and HIF1A. The druggable targets ERBB2 (Her2), MET, and the HIF pathway, as well as several other potential pharmacogenetic indicators (including EBV infection itself, as well as SPARC, TYMS, FCGR2B and REG4) were identified in some tumor specimens.ConclusionThis study shows how modern molecular technology applied to archival fixed tissues yields novel insights into viral oncogenesis that could be useful in managing affected patients.

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A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma

Abstract: The link between EBV infection and

Cited by 14 publications

References 44 publications

Suppression of the LMP2A target gene, EGR‐1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle

Suppression of the LMP2A target gene, EGR‐1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle

Epstein-Barr Virus LMP2A Reduces Hyperactivation Induced by LMP1 to Restore Normal B Cell Phenotype in Transgenic Mice

Epstein-barr virus infected gastric adenocarcinoma expresses latent and lytic viral transcripts and has a distinct human gene expression profile

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