Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma

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Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma. / Lupino, Lauren; Perry, Tracey; Margielewska, Sandra; Hollows, Robert; Ibrahim, Maha; Care, Matthew; Allegood, Jeremy; Tooze, Reuben; Sabbadini, Roger; Reynolds, Gary; Bicknell, Roy; Rudzki, Zbigniew; Lin Hock, Ye; Zanetto, Ulises; Wei, Wenbin; Simmons, William; Spiegel, Sarah; Woodman, Ciaran B J; Rowe, Martin; Vrzalikova, Katerina; Murray, Paul G.

In: Leukemia, Vol. 33, No. 12, 12.2019, p. 2884-2897.

Research output: Contribution to journalArticle

Harvard

Lupino, L, Perry, T, Margielewska, S, Hollows, R, Ibrahim, M, Care, M, Allegood, J, Tooze, R, Sabbadini, R, Reynolds, G, Bicknell, R, Rudzki, Z, Lin Hock, Y, Zanetto, U, Wei, W, Simmons, W, Spiegel, S, Woodman, CBJ, Rowe, M, Vrzalikova, K & Murray, PG 2019, 'Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma', Leukemia, vol. 33, no. 12, pp. 2884-2897. https://doi.org/10.1038/s41375-019-0478-9

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Author

Lupino, Lauren ; Perry, Tracey ; Margielewska, Sandra ; Hollows, Robert ; Ibrahim, Maha ; Care, Matthew ; Allegood, Jeremy ; Tooze, Reuben ; Sabbadini, Roger ; Reynolds, Gary ; Bicknell, Roy ; Rudzki, Zbigniew ; Lin Hock, Ye ; Zanetto, Ulises ; Wei, Wenbin ; Simmons, William ; Spiegel, Sarah ; Woodman, Ciaran B J ; Rowe, Martin ; Vrzalikova, Katerina ; Murray, Paul G. / Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma. In: Leukemia. 2019 ; Vol. 33, No. 12. pp. 2884-2897.

Bibtex

@article{9324f5fc613d4d0f96235c8ea5285699,
title = "Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma",
abstract = "Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.",
author = "Lauren Lupino and Tracey Perry and Sandra Margielewska and Robert Hollows and Maha Ibrahim and Matthew Care and Jeremy Allegood and Reuben Tooze and Roger Sabbadini and Gary Reynolds and Roy Bicknell and Zbigniew Rudzki and {Lin Hock}, Ye and Ulises Zanetto and Wenbin Wei and William Simmons and Sarah Spiegel and Woodman, {Ciaran B J} and Martin Rowe and Katerina Vrzalikova and Murray, {Paul G}",
year = "2019",
month = "12",
doi = "10.1038/s41375-019-0478-9",
language = "English",
volume = "33",
pages = "2884--2897",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "12",

}

RIS

TY - JOUR

T1 - Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma

AU - Lupino, Lauren

AU - Perry, Tracey

AU - Margielewska, Sandra

AU - Hollows, Robert

AU - Ibrahim, Maha

AU - Care, Matthew

AU - Allegood, Jeremy

AU - Tooze, Reuben

AU - Sabbadini, Roger

AU - Reynolds, Gary

AU - Bicknell, Roy

AU - Rudzki, Zbigniew

AU - Lin Hock, Ye

AU - Zanetto, Ulises

AU - Wei, Wenbin

AU - Simmons, William

AU - Spiegel, Sarah

AU - Woodman, Ciaran B J

AU - Rowe, Martin

AU - Vrzalikova, Katerina

AU - Murray, Paul G

PY - 2019/12

Y1 - 2019/12

N2 - Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.

AB - Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.

UR - http://www.scopus.com/inward/record.url?scp=85066035341&partnerID=8YFLogxK

U2 - 10.1038/s41375-019-0478-9

DO - 10.1038/s41375-019-0478-9

M3 - Article

C2 - 31097785

VL - 33

SP - 2884

EP - 2897

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 12

ER -