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.

Department of Biochemistry and Molecular Biology and Massey Cancer Center Virginia Commonwealth University School of Medicine Richmond VA USA

Department of Cellular Pathology John Radcliffe Hospital Oxford UK

Department of Clinical and Molecular Pathology Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Pathology Universiti Putra Malaysia Selangor Malaysia

Institute of Anatomy and Cell Biology Georg August University of Göttingen Göttingen Germany

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

Erratum In

Leukemia. 2019 Aug;33(8):2126. doi: 10.1038/s41375-019-0511-z. PubMed

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