Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma

Wasik, Agata M.; Wu, Chenglin; Mansouri, Larry; Rosenquist, Richard; Pan‐Hammarström, Qiang; Sander, Birgitta

doi:10.1182/bloodadvances.2017014860

Cited by 11 publications

(6 citation statements)

References 26 publications

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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][4][5][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].…”

Section: Introductionmentioning

confidence: 85%

Evaluation of S1PR1, pSTAT3, S1PR2, and FOXP1 expression in aggressive, mature B cell lymphomas

2019

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Aggressive, mature B cell lymphomas include Burkitt lymphoma (BL); high-grade B cell lymphomas (HGBL) (e.g., 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 (DLBCL). Overlapping morphologic and immunohistochemical features of these lymphomas pose diagnostic challenges in some cases, and better understanding of potential diagnostic biomarkers and possible therapeutic targets is needed. Sphingosine 1 phosphate receptors (S1PR1-5) are G protein-coupled receptors that bind S1P and influence migration and survival in multiple 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 in DLBCL. Our aim was to extend the understanding of S1PR1, STAT3, and S1PR2, FOXP1 expression beyond DLBCL, into additional aggressive, mature B cell lymphomas using immunohistochemical expression analysis of human tissue samples. S1PR1 and S1PR2 showed different expression patterns in mantle zones and follicle centers in reactive lymphoid tissue. BL showed a unique expression pattern compared to HGBL and DLBCL. Additionally, S1PR1 and S1PR2 expression were typically mutually exclusive and were expressed in a low proportion of cases (frequently HGBL involving extranodal sites). FOXP1 was expressed in a high proportion of various case types and pSTAT3 was detected in a significant proportion of HGBL and DLBCL. These findings provide further evidence that S1PR1, pSTAT3, S1PR2, and FOXP1 play a role in a subset of aggressive, mature B cell lymphomas.

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Section: Introductionmentioning

confidence: 85%

Evaluation of S1PR1, pSTAT3, S1PR2, and FOXP1 expression in aggressive, mature B cell lymphomas

2019

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“…High surface S1PR1 levels facilitate mobilization of B-cells from these niches into the circulation. MCL cells express high surface levels of S1PR1 [48], and low S1PR1 expression contributes to retention within microenvironmental niches [54], likely promoting tumor cell survival. Consistently, our results showed that S1PR1 is expressed on both JeKo-1 and REC-1 cells, albeit at higher levels on REC-1 cells, as shown previously [48], and its attenuation enhanced the capacity for JeKo-1 and REC-1 cells to adhere to stromal cells.…”

Section: Discussionmentioning

confidence: 99%

Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells

Sadeghi

Arvidsson

Merrien

et al. 2020

Cancers

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Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, displaying different patterns of stromal cell adhesion and chemotaxis towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. Five-hundred and ninety genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR using siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1, but not REC-1 cells. Cell surface levels of chemokine receptor CXCR4 were higher in JeKo-1, facilitating migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 played a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. Our results provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs.

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“…Thus, retention of MCL in the supportive microenvironment could represent a residual reservoir of cancer cells linked to relapse. It remains to be determined whether S1P 1 inactivating mutations can reduce ibrutinib sensitivity in MCL [32]. However, chemotherapeutic resistance is associated with enhanced adhesion of MCL to the stroma and ibrutinib increases expression of S1P 1 , while decreasing CCR7 levels in chronic lymphocytic leukaemia.…”

Section: Role Of S1p In Tumour Neovascularisation and Metastasismentioning

confidence: 99%

Recent advances in the role of sphingosine 1‐phosphate in cancer

Pyne

2020

FEBS Letters

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Sphingosine 1-phosphate (S1P) is a bioactive lipid that binds to a family of G protein-coupled receptors (S1P 1-5) and intracellular targets, such as HDAC1/ 2, that are functional in normal and pathophysiologic cell biology. There is a significant role for sphingosine 1-phosphate in cancer underpinning the socalled hallmarks, such as transformation and replicative immortality. In this review, we survey the most recent developments concerning the role of sphingosine 1-phosphate receptors, sphingosine kinase and S1P lyase in cancer and the prognostic indications of these receptors and enzymes in terms of diseasespecific survival and recurrence. We also provide evidence for identification of new therapeutic approaches targeting sphingosine 1-phosphate to prevent neovascularisation, to revert aggressive and drug-resistant cancers to more amenable forms sensitive to chemotherapy, and to induce cytotoxicity in cancer cells. Finally, we briefly describe current advances in the development of isoform-specific inhibitors of sphingosine kinases for potential use in the treatment of various cancers, where these enzymes have a predominant role. This review will therefore highlight sphingosine 1-phosphate signalling as a promising translational target for precision medicine in stratified cancer patients.

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Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma

Abstract: Key Points S1PR1 mutations are present in 7.8% of patients with MCL and are significantly more frequent at relapse. S1PR1 mutations reduce expression of the S1PR1 receptor, which mediates migration towards the tissue-to-blood egress factor S1P in MCL.

Cited by 11 publications

References 26 publications

Evaluation of S1PR1, pSTAT3, S1PR2, and FOXP1 expression in aggressive, mature B cell lymphomas

Evaluation of S1PR1, pSTAT3, S1PR2, and FOXP1 expression in aggressive, mature B cell lymphomas

Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells

Recent advances in the role of sphingosine 1‐phosphate in cancer

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