Expression of sphingosine-1-phosphate receptor 1 in mantle cell lymphoma

Abstract

The distribution and pathological significance of sphingosine-1-phosphate receptor 1 expression are still unclear. In this study, we evaluated sphingosine-1-phosphate receptor 1's suitability as a diagnostic marker for malignant lymphoma by immunostaining formalin-fixed paraffin-embedded sections using a well-defined commercial anti-sphingosine-1-phosphate receptor 1 antibody. Sphingosine-1-phosphate receptor 1 was strongly expressed on the surface of small lymphocytes forming primary lymphoid follicles and in the mantle zone of secondary lymphoid follicles. Microarray-based immunohistochemistry with tissue samples from 85 lymphoid malignancy cases demonstrated that sphingosine-1-phosphate receptor 1 was expressed on the surface of mantle cell lymphoma cells. Strong expression was observed in all classical mantle cell lymphoma cases involving the lymph node (19 out of 19), gastrointestinal tract (10 out of 10), bone marrow (9 out of 9), and orbita (1 out of 1). Good results were obtained even in sections where cyclin D1 signals were lost because of over-fixation and/or decalcification. One aggressive variant of mantle cell lymphoma displayed a weaker membranous staining than classical mantle cell lymphoma in the lymph node and bone marrow. In a cyclin D1-negative mantle cell lymphoma of the orbita, no conclusive result was obtained. No cases of follicular lymphoma, marginal zone lymphoma, B lymphoblastic leukemia/lymphoma, or Burkitt's lymphoma showed any significant expression, whereas 2 out of 6 chronic lymphocytic leukemia/small lymphocytic lymphomas in bone marrow, 1 out of 3 lymphoplasmacytic lymphomas in the lymph node, and 2 out of 37 diffuse large B-cell lymphomas exhibited staining. A quantitative reverse transcription polymerase chain reaction-based analysis of mantle cell lymphoma lines revealed the sphingosine-1-phosphate receptor 1 mRNA expression level to be well correlated with the results of immunocytochemistry, flow cytometry, and western blotting. Thus, sphingosine-1-phosphate receptor 1 immunohistochemistry may be useful in the histological diagnosis of mantle cell lymphoma with formalin-fixed and paraffin-embedded sections. The antigen may be particularly valuable in cases where cyclin D1 immunostaining is not successful.

Cellular Localization of Sphingosine-1-phosphate Receptor 1 Expression in the Human Central Nervous System

“…This antibody (1:50 dilution) has been thoroughly checked for specificity by comparing the immunostaining results of the vasculature in paraffin sections of S1PR1 2/2 and S1PR1 1/2 mouse embryos, an angiosarcoma cell line (ISO-HAS), and mantle cell lymphoma expressing considerable quantities of S1PR1 mRNA (Akiyama et al 2008;Nishimura et al 2010). A prediluted rabbit antiglial fibrillary acidic protein (GFAP) antibody (Nichirei; Tokyo, Japan), polyclonal antibody against aquaporin 4 (AQP4, 1:400 dilution; Millipore, Billerica, MA), and synaptophysin (1:400 dilution; Biogene, Montreal, Canada) were also used.…”

“…The S1PR1 antigen was stable even in autopsy samples after long-standing fixation and could be used as an immunohistochemical marker (Akiyama et al 2008(Akiyama et al ,2009Nishimura et al 2010). In this study, to clarify the expression of S1PR1 in the human CNS, we investigated postmortem specimens by IHC, immunoelectron microscopy, Western blotting (WB), and quantitative real-time RT-PCR.…”

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2009 to January 2010

“…Another candidate antigen might be even more specific for MCL, but the results are far from complete. According to Nishimura et al [44], sphingosine-1-phosphate receptor 1 has membrane expression in MCL normal mantle zone cells and in all classical mantle cell lymphoma cases involving the lymph node (19 out of 19), gastrointestinal tract (10 out of 10), bone marrow (nine out of nine), and orbita (one out of one). Good results were obtained even in sections where cyclin D1 signals were lost because of over-fixation and/or decalcification.…”

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

“…In diffuse large B-cell lymphoma (DLBCL), the expression of S1PR2 is disturbed either because of mutations (in germinal center B-cell subtype DLBCL) 13,14 or suppression by the transcription factor FOXP1 (in activated B-cell subtype DLBCL) 15 and contributes to the pathogenesis of DLBCL. S1PR1 controls egress of lymphocytes to the blood and lymph 16 and is expressed in normal mantle zone B cells but also in MCL, 10,11 suggesting that this receptor might have a specific function for mantle zone B cells and their malignant counterparts. Although few mutations have been hitherto identified in homing/egress receptors, we recently reported S1PR1 as 1 of 25 recurrent mutations by whole exome sequencing (WES) and Sanger sequencing of primary and relapsed tumors from 13 MCLs.…”

“…6,7 Several receptors responsible for MCL cell localization within the tissue microenvironment have been reported including integrins and homing receptors, such as CXCR4, CXCR5, 8 CCR7, 9 and sphingosine-1-phosphate receptor 1 (S1PR1). 10,11 The importance of the microenvironment was recently reinforced by drugs targeting B-cell receptor signaling (eg, the Bruton tyrosine kinase inhibitor ibrutinib, which was shown to be effective in MCL). 12 Sphingosine-1-phosphate (S1P) is a sphingolipid that regulates migration of lymphocytes through a concentration gradient with 10 0003 higher levels in blood and lymph compared with tissue.…”