Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1,2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells3,4. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor’s Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt’s lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-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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We thank S. Coughlin for Gna13f/f and Arhgef1−/− mice and R. Proia for S1pr2−/− mice. We thank X. Geng and G. Doitsch for assistance with processing of human tonsil, A. Reboldi for discussion, and T. Arnon and O. Bannard for reading the manuscript. J.R.M. is supported by a Fellow Award from the Leukemia & Lymphoma Society and by National Institutes of Health (NIH) institutional training grants (T32 DK007636 and T32 CA1285835); R.S. is supported by the Dr Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). N.V. was supported by NIH grant GM097261 for the modelling work. J.G.C. is an Investigator of the Howard Hughes Medical Institute. The human lymphoma samples were studied under the auspices of the Lymphoma/Leukemia Molecular Profiling Project. The work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and NIH grant AI45073.
Extended data figures
This file contains Supplementary Text, Supplementary References and Supplementary Tables 1-4.