Germinal centre B-cell-like diffuse largeB-cell lymphoma(GCB-DLBCL) is a commonmalignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2.Workinmice showedthat sphingosine-1-phosphate receptor-2 (S1PR2), aGa12 andGa13 coupled receptor, promotes growth regulation andlocal confinement of germinal centreBcells3,4.Recent deep sequencing studies ofGCB-DLBCL have revealedmutations inmany genes in this cancer, including inGNA13 (encodingGa13) andS1PR2 (refs 5-7). Here weshow, usingin vitro andin vivo assays, thatGCBDLBCL-associatedmutations occurring in S1PR2frequentlydisrupt the receptor'sAkt andmigration inhibitory functions.Ga13-deficient mouse germinal centre B cells and humanGCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Ga13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centreBcells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency inGa13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood.GCB-DLBCL cell lines frequently carriedmutations in theGa13 effectorARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Ga13-and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derivedmalignancy,Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Ga13.These findings identify aGa13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.
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