Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC subtype diffuse large B cell lymphoma.

Vockerodt, Martina and Vrzalikova, Katerina and Ibrahim, Maha and Nagy, Eszter and Margielewska, Sandra and Hollows, Robert and Lupino, Lauren and Tooze, Reuben and Care, Matthew and Simmons, William and Schrader, Alexandra and Perry, Tracey and Abdullah, Maizaton and Foster, Stephen and Reynolds, Gary and Dowell, Alexander and Rudski, Zbigniew and Krappmann, Daniel and Kube, Dieter and Woodman, Ciaran and Wei, Wenbin and Taylor, Graham and Murray, Paul G (2019) Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC subtype diffuse large B cell lymphoma. The Journal of pathology. ISSN 1096-9896. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Official URL: https://onlinelibrary.wiley.com/doi/10.1002/path.5...

Abstract

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 focussed on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCL 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-DLBCL 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. This article is protected by copyright. All rights reserved.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: QW Microbiology. Immunology
QZ Pathology. Oncology
Divisions: Clinical Support > Pathology
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Depositing User: Jennifer Manders
Date Deposited: 08 Feb 2019 14:30
Last Modified: 08 Feb 2019 14:30
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/1828

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