The sphingosine-1-phosphate receptor S1PR2 and its downstream signaling pathway is commonly silenced in diffuse large B-cell lymphoma (DLBCL), either by mutational inactivation or through negative regulation by the oncogenic transcription factor FOXP1. In this study, we have examined the upstream regulators of S1PR2 expression and have newly identified the TGF-β/TGF-βR2/SMAD1 axis as critically involved in S1PR2 transcriptional activation. Phosphorylated SMAD1 directly binds to regulatory elements in the locus as assessed by chromatin immunoprecipitation, and the CRISPR-mediated genomic editing of , or in DLBCL cell lines renders cells unresponsive to TGF-β-induced apoptosis. DLBCL clones lacking any one of the three factors have a clear growth advantage in vitro, as well as in subcutaneous xenotransplantation models, and in a novel model of orthotopic growth of DLBCL cells in the spleens and bone marrow of MISTRG mice expressing various human cytokines. The loss of induces hyper-proliferation of the germinal center B-cell compartment of immunized mice and accelerates -driven lymphomagenesis in spontaneous and serial transplantation models. The specific loss of in murine GC B-cells phenocopies the effects of loss on GC B-cell hyper-proliferation. Finally, we show that SMAD1 expression is aberrantly downregulated in >85% of analyzed DLBCL patients. The combined results uncover an important novel tumor suppressive function of the TGF-β/TGF-βR2/SMAD1/S1PR2 axis in DLBCL, and show that DLBCL cells have evolved to inactivate the pathway at the level of SMAD1 expression.