Background: The presence of circulating plasma cells (cPCs) was associated with a worse prognosis in multiple myeloma patients. However, the underlying mechanisms involved in the migration and invasion of bone marrow myeloma cells (BMMCs) to cPCs remains unclear. Here, we investigate the possible factors related to hematogenous myeloma cell dissemination and potential regulatory mechanisms.
Methods: BMMCs and cPCs of five extramedullary plasmacytoma (EMP) patients were selected for single cell RNA sequencing, We found that the expression level of sphingosine-1-phosphate receptor 2 (S1RP2 ) was lower in cPCs compared with that in BMMCs. Then, we investigated the effect of S1PR2 in cell migration and invasion through pharmacologic inhibition with a S1PR2 -selective antagonist JTE-013 or knockdown of S1PR2  expression in MM cell line U266.
Results: The results showed that S1PR2  inhibition with JTE-013 or S1PR2 -shRNA significantly promoted cell migration and invasion in U266 cells. We measured the expression of invasion-related proteins by Western blot and found that knockdown of S1PR2  could reduce MMP-9 expression in U266 cells. Furthermore, we found NF-κB pathway may mediate the inhibition effects of S1PR2  on cell migration and invasion in MM cells.
Conclusion: Our findings demonstrated that S1PR2  downregulation may contribute to the initial extramedullary translocation by promoting cell migration and invasion through NF-κB pathway activation.
Keywords: multiple myeloma, extramedullary plasmacytoma, circulating plasma cells, NF-κB, S1PR2