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

Vrzalikova, Katerina; Ibrahim, Maha; Vockerodt, Martina; Perry, Tracey; Margielewska, Sandra; Lupino, Lauren; Nagy, Eszter; Soilleux, Elizabeth; Liebelt, David A.; Hollows, Robert; Last, A; Reynolds, Gary; Abdullah, Md. Pauzi; Curley, Helen; Care, Matthew A.; Krappmann, Daniel; Tooze, Reuben; Allegood, Jeremy C.; Spiegel, Sarah; Wei, Wenbin; Woodman, Ciarán; Murray, Paul G.

doi:10.1038/leu.2017.275

Cited by 26 publications

(34 citation statements)

References 56 publications

(76 reference statements)

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“…Sphingosine 1 Phosphate Receptors (S1PR1-5) represent a family of G-protein coupled receptors that bind the sphingolipid (S1P) and influence migration and survival pathways in a variety of cell types; S1PRs are emerging as biomarkers in B cell lymphomas 3–6 and B cell development 7 . Our prior work, which demonstrated S1PR1 expression in a subset of Classic Hodgkin Lymphoma cases 8 , has recently been supported by others 9 . Additional studies indicate that S1PR expression may influence anatomic location/distribution in a variety of types of lymphoma 10 .…”

Section: Introductionsupporting

confidence: 67%

Evaluation of S1PR1/pSTAT3 and S1PR2/FOXP1 Expression in Aggressive, Mature B Cell Lymphomas

Al-Kawaaz

Sánchez

Kluk

2018

Preprint

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Aggressive, mature B-cell lymphomas represent a heterogeneous group of diseases including Burkitt Lymphoma (BL), High Grade B Cell Lymphomas (HGBL) (eg, Double-Hit B cell lymphomas (HGBL-DH: HGBL with MYC and BCL2 and/or BCL6 translocations)), HGBL, Not Otherwise Specified (HGBL, NOS) and Diffuse Large B Cell Lymphoma.The overlapping morphologic and immunohistochemical features of these lymphomas may pose diagnostic challenges in some cases, and a better understanding of potential diagnostic biomarkers and possible therapeutic targets is needed. Sphingosine 1 Phosphate Receptors (S1PR1-5) represent a family of G-protein coupled receptors that bind the sphingolipid (S1P) and influence migration and survival pathways in a variety of cell types, including lymphocytes. S1PRs are emerging as biomarkers in B cell biology and interaction between S1PR pathways and STAT3 or FOXP1 has been reported, especially in DLBCL.Our aim was to extend the understanding of the S1PR1, STAT3 and S1PR2, FOXP1 expression beyond DLBCL, into additional aggressive, mature B cell lymphomas such as BL, HGBL-DH and HGBL,NOS.Herein, we report that S1PR1 and S1PR2 showed different patterns of expression in mantle zones and follicle centers in reactive lymphoid tissue and, among the lymphomas in this study, Burkitt lymphomas showed a unique pattern of expression compared to HGBL and DLBCL. Additionally, we found that S1PR1 and S1PR2 expression was typically mutually exclusive and were expressed in a low proportion of cases (predominantly HGBL involving extranodal sites). Lastly, FOXP1 was expressed in a high proportion of the various case types and pSTAT3 was detected in a significant proportion of HGBL and DLBCL cases. Taken together, these findings provide further evidence that S1PR1, pSTAT3, S1PR2 and FOXP1 play a role in a subset of aggressive mature B cell lymphomas.STAT3 is a transcription factor which regulates tumorigenesis in a variety of lymphoproliferative disorders and is therapeutically targetable 11, 12 . pSTAT3 has been reported to be a potential biomarker in DLBCL which may depend on anatomic location, according to one study 13 . STAT3 was reported to show high levels of expression and phosphorylation in ABC-DLBCL 14 . Interestingly, STAT3 was found to be a direct transcriptional activator of S1PR1 expression in various cell types 15 . In DLBCL, S1PR1 over-expression has been reported in approximately 6-40% of DLBCL and was associated with STAT3 phosphorylation in fresh tissue and as well as a negative prognosis 5, 16 . Additional studies, using primary tumor cells, have also shown phospho-STAT3 activity correlated with increased S1PR1 expression in ABC-DLBCL 17 , and that S1PR1 could activate STAT3 in ABC-DLBCL 17 .Furthermore, inhibition of S1PR1 expression, down-regulated STAT3 activity and caused growth inhibition of lymphoma cells 17 . In BL, phosphorylated STAT3 was reported to be associated with multidrug resistance according to one study 18 , however, the expression of phosphorylated STAT3does not appear to have been adequ...

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Section: Introductionsupporting

confidence: 67%

Evaluation of S1PR1/pSTAT3 and S1PR2/FOXP1 Expression in Aggressive, Mature B Cell Lymphomas

Al-Kawaaz

Sánchez

Kluk

2018

Preprint

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“…The complex interactions of sphingolipids with nuclear gene regulation suggest close links between these pathways, but detailed understanding is missing. The ability of the sphingosine mimetic drug FTY720/fingolimod to modulate gene expression in neurons and astrocytes [38,39] is probably due in large part to the links observed between S1P receptor signaling and the activities of crucial transcription factors including NF-κB, Yin-Yang-1, or Notch [71][72][73][74][75]. However, the inhibition of class I HDACs by FTY720 / FTY720P must also be considered a potential mechanism [41,42].…”

Section: Discussionmentioning

confidence: 99%

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

et al. 2018

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Sphingolipid signaling disturbances correlate with Alzheimer's disease (AD) progression. We examined the influence of FTY720/fingolimod, a sphingosine analog and sphingosine-1-phosphate (S1P) receptor modulator, on the expression of sphingolipid metabolism and signaling genes in a mouse transgenic AD model. Our results demonstrated that AβPP (V717I) transgene led with age to reduced mRNA expression of S1P receptors (S1PRs), sphingosine kinase SPHK2, ceramide kinase CERK, and the anti-apoptotic Bcl2 in the cerebral cortex and hippocampus, suggesting a pro-apoptotic shift in 12-month old mice. These changes largely emulated alterations we observed in the human sporadic AD hippocampus: reduced SPHK1, SPHK2, CERK, S1PR1, and BCL2. We observed that the responses to FTY720 treatment were modified by age and notably differed between control (APP − ) and AD transgenic (APP + ) animals. AβPP (V717I)-expressing 12-month-old animals reacted to fingolimod with wide changes in the gene expression program in cortex and hippocampus, including increased pro-survival SPHKs and CERK. Moreover, BCL2 was elevated by FTY720 in the cortex at all ages (3, 6, 12 months) while in hippocampus this increase was observed at 12 months only. In APP − mice, fingolimod did not induce any significant mRNA changes at 12 months. Our results indicate significant effect of FTY720 on the age-dependent transcription of genes involved in sphingolipid metabolism and pro-survival signaling, suggesting its neuroprotective role in AD animal model.

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“…Re-analysis of two large expression datasets confirmed the down-regulation of S1PR2 in DLBCL compared to normal GC B cells, and showed that this was particularly pronounced in ABC-DLBCL ( Figure 3A) [38,[41][42][43]. To study the relationship between the expression of S1PR2 and LMP1 in primary tumours we performed IHC using an antibody that we previously showed is specific for S1PR2 [46]. In contrast to GC B cells which expressed S1PR2, 114/167 DLBCL showed no tumour cell S1PR2 expression ( Figure 3B).…”

Section: Down-regulation Of S1pr2 In Lmp1-expressing Primary Dlbclmentioning

confidence: 74%

“…Green, UK; NEL791001KT) [46]. Antibody stripping by microwaving in pH 6 citrate buffer was used between steps.…”

Section: Protein Analysis and In Situ Hybridizationmentioning

confidence: 99%

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

Vockerodt

Vrzalikova

Ibrahim

et al. 2019

The Journal of Pathology

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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 downregulation 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.KEY WORDS: S1P, S1PR2, EBV, LMP1, CD40 and DLBCL This article

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

Cited by 26 publications

References 56 publications

Evaluation of S1PR1/pSTAT3 and S1PR2/FOXP1 Expression in Aggressive, Mature B Cell Lymphomas

Evaluation of S1PR1/pSTAT3 and S1PR2/FOXP1 Expression in Aggressive, Mature B Cell Lymphomas

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

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

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