Document Detail


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.
MedLine Citation:
PMID:  21411757     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Katerina Vrzalikova; Martina Vockerodt; Sarah Leonard; Andrew Bell; Wenbin Wei; Alexandra Schrader; Kenneth L Wright; Dieter Kube; Martin Rowe; Ciaran B Woodman; Paul G Murray
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-16
Journal Detail:
Title:  Blood     Volume:  117     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-03     Completed Date:  2011-09-08     Revised Date:  2013-10-24    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5907-17     Citation Subset:  AIM; IM    
Affiliation:
School of Cancer Sciences, University of Birmingham, Vincent Drive, Birmingham, UK.
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MeSH Terms
Descriptor/Qualifier:
B-Lymphocytes / metabolism,  virology*
Blotting, Western
Cell Differentiation*
Cell Transformation, Viral
Cells, Cultured
Child
Epstein-Barr Virus Infections / complications,  genetics,  virology
Gene Expression Profiling
Germinal Center
Herpesvirus 4, Human / physiology*
Humans
Immunoenzyme Techniques
Lymphoma, B-Cell / etiology*,  pathology
Oligonucleotide Array Sequence Analysis
Palatine Tonsil / cytology,  metabolism
Plasma Cells / metabolism,  pathology*
RNA, Messenger / genetics
Repressor Proteins / genetics,  metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Tumor Markers, Biological / genetics,  metabolism
Viral Matrix Proteins / genetics,  metabolism*
Virus Latency
Virus Replication
Grant Support
ID/Acronym/Agency:
R01 CA114504/CA/NCI NIH HHS; R01 CA114504-05/CA/NCI NIH HHS; //Cancer Research UK
Chemical
Reg. No./Substance:
0/EBV-associated membrane antigen, Epstein-Barr virus; 0/RNA, Messenger; 0/Repressor Proteins; 0/Tumor Markers, Biological; 0/Viral Matrix Proteins; 138415-26-6/PRDM1 protein, human
Comments/Corrections
Comment In:
Blood. 2011 Jun 2;117(22):5790-1   [PMID:  21636716 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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