title: Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas.
abstract: An important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication, which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation toward plasma cells, we asked whether the physiologic signals that drive normal B-cell differentiation are absent in EBV-transformed cells. We focused on BLIMP1α, a transcription factor that is required for plasma cell differentiation and that is inactivated in diffuse large B-cell lymphomas. We show that BLIMP1α expression is down-regulated after EBV infection of primary germinal center B cells and that the EBV oncogene, latent membrane protein-1 (LMP-1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP-1 was accompanied by a partial disruption of the BLIMP1α transcriptional program, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP-1 expression in progenitor germinal center B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α, in turn preventing plasma cell differentiation and induction of the viral lytic cycle.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Vincent Drive, Birmingham, UK.
authors.forename: Katerina
authors.initials: K
authors.lastname: Vrzalikova
authors.forename: Martina
authors.initials: M
authors.lastname: Vockerodt
authors.forename: Sarah
authors.initials: S
authors.lastname: Leonard
authors.forename: Andrew
authors.initials: A
authors.lastname: Bell
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schrader
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Wright
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 / Q000821:virology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002648:Child; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics / Q000821:virology; D020869:Gene Expression Profiling; D018858:Germinal Center; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D014066:Palatine Tonsil / Q000166:cytology / Q000378:metabolism; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D014408:Biomarkers, Tumor; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D012333:RNA, Messenger; D012097:Repressor Proteins; D014763:Viral Matrix Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1