Schematic summarizing the tumor-suppressive properties of the TGF-β/SMAD1/S1PR2 axis in DLBCL. Under physiological conditions, centrocytes and centroblasts express large amounts of S1PR2, which promotes GC confinement because of a gradient of S1P that increases in concentration toward the borders of the GC and leads to apoptosis in GC cells that attempt to exit the GC. In DLBCL, S1PR2 is either mutated (in the GCB subtype) or transcriptionally downregulated by FOXP1 (in the ABC subtype). Loss of S1PR2 thus is an early initiating event in both major subtypes of DLBCL. The expression of S1PR2 is further regulated by TGF-β, which binds to its receptor TGF-βR2 and activates SMAD1 phosphorylation and nuclear translocation. p-SMAD1 binds directly to regulatory elements in the S1PR2 promoter and activates S1PR2 expression; most cases of DLBCL exhibit aberrantly low or absent expression of SMAD1.