Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC-subtype diffuse large B-cell lymphoma
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
17723
Cancer Research UK - United Kingdom
PubMed
30666658
DOI
10.1002/path.5237
Knihovny.cz E-resources
- Keywords
- CD40, DLBCL, EBV, LMP1, S1P, S1PR2,
- MeSH
- Phosphatidylinositol 3-Kinase metabolism MeSH
- CD40 Antigens genetics metabolism MeSH
- Databases, Genetic MeSH
- Lymphoma, Large B-Cell, Diffuse genetics metabolism mortality virology MeSH
- Epstein-Barr Virus Infections mortality virology MeSH
- Host-Pathogen Interactions MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Prognosis MeSH
- Viral Matrix Proteins genetics metabolism MeSH
- Proto-Oncogene Proteins c-akt metabolism MeSH
- Sphingosine-1-Phosphate Receptors genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Signal Transduction MeSH
- Cell Transformation, Viral MeSH
- Herpesvirus 4, Human genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Phosphatidylinositol 3-Kinase MeSH
- CD40 Antigens MeSH
- EBV-associated membrane antigen, Epstein-Barr virus MeSH Browser
- Viral Matrix Proteins MeSH
- Proto-Oncogene Proteins c-akt MeSH
- Sphingosine-1-Phosphate Receptors MeSH
- S1PR2 protein, human MeSH Browser
The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Department of Histopathology Heartlands Hospital Birmingham UK
Department of Pathology Universiti Putra Malaysia Seri Kembangan Malaysia
Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK
Institute of Immunology and Immunotherapy University of Birmingham Birmingham UK
Leeds Institute of Cancer and Pathology University of Leeds Leeds UK
Research Unit Cellular Signal Integration Helmholtz Zentrum München Neuherberg Germany
Sheffield Institute of Translational Neuroscience University of Sheffield Sheffield UK
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