title: Suppression of the LMP2A target gene, EGR-1, protects Hodgkin's lymphoma cells from entry to the EBV lytic cycle.
abstract: 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.
authors.affiliation: School of Cancer Sciences, University of Birmingham, UK. m.vockerodt@bham.ac.uk
authors.forename: Martina
authors.initials: M
authors.lastname: Vockerodt
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.forename: Eszter
authors.initials: E
authors.lastname: Nagy
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Prouzova
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schrader
authors.forename: Dieter
authors.initials: D
authors.lastname: Kube
authors.forename: Martin
authors.initials: M
authors.lastname: Rowe
authors.forename: Ciaran B
authors.initials: CB
authors.lastname: Woodman
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006689:Hodgkin Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D011947:Receptors, Antigen, B-Cell; D015534:Trans-Activators; D014763:Viral Matrix Proteins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: B cell receptor; Epstein-Barr virus; Hodgkin's lymphoma; germinal centre; latent membrane protein 2A; lytic cycle