Loss of signaling via Gα13 in germinal center B cell-derived lymphoma

Germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL) is a common malignancy yet the signaling pathways deregulated and the factors leading to its systemic dissemination are poorly defined(1,2). Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of GC B cells(3,4). Recent GCB-DLBCL deep sequencing studies have revealed mutations in a large number of genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2(5-7). 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 GC B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed GC B cell-derived lymphoma. GC B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to GC 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 GC 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 GC B cell-derived malignancy, Burkitt lymphoma (BL), also represses GC 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 GC B cells that is frequently disrupted in GC B cell-derived lymphoma.