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S1PR1 drives a feedforward signaling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells


Vrzalikova, K. and Ibrahim, M. and Vockerodt, M. and Perry, T. and Margielewska, S. and Lupino, L. and Nagy, E. and Soilleux, E. and Liebelt, D. and Hollows, R. and Last, A. and Reynolds, G. and Abdullah, M. and Curley, H. and Care, M. and Krappmann, D. and Tooze, R. and Allegood, J. and Spiegel, S. and Wei, W. and Woodman, C. B. J. and Murray, P. G. (2017) S1PR1 drives a feedforward signaling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells. Leukemia, 32. pp. 214-223. ISSN 0887-6924; ESSN: 1476-5551


The Hodgkin/Reed–Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.

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Additional Metadata

Item Type: Article
Divisions: Faculty of Medicine and Health Science
DOI Number: https://doi.org/10.1038/leu.2017.275
Publisher: Springer Nature Limited
Keywords: Hodgkin lymphoma; Lymphoid; Sphingosine-1-phosphate (S1P); Sphingosine kinase 1 (SPHK1)
Depositing User: Mohd Hafiz Che Mahasan
Date Deposited: 20 Aug 2018 02:04
Last Modified: 20 Aug 2018 02:04
Altmetrics: http://www.altmetric.com/details.php?domain=psasir.upm.edu.my&doi=10.1038/leu.2017.275
URI: http://psasir.upm.edu.my/id/eprint/63162
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