Mutations in the Gα13 Pathway Promote GCB-DLBCL Progression

Germinal center (GC) B cells are tightly regulated in terms of their growth and localization to the GC niche, in part via the Gα12- and Gα13-coupled receptor sphinogosine-1-phosphate receptor 2 (S1PR2). This regulation is disrupted in germinal center B-cell–like diffuse large B-cell lymphoma (GCB-DLBCL), a malignancy characterized by the expansion and systemic dissemination of GC B cells. Muppidi and colleagues found that mutations in S1PR2 in GCB-DLBCL samples disrupted S1PR2 expression and its ability to inhibit AKT activation and cell migration. In addition, loss of guanine nucleotide–binding protein α13 (GNA13), which encodes Gα13 and was also frequently mutated in GCB-DLBCL samples, increased AKT activation, enhanced the survival of GC B cells, and induced formation of GC-derived B-cell lymphomas. Inactivating mutations in the Gα13 effector RHO guanine nucleotide exchange factor 1 (ARHGEF1) were also detected in GCB-DLBCL cell lines. Deficiency in either ARHGEF1 or Gα13 triggered disruption of GC architecture and facilitated GC B-cell egress to the lymph and blood, whereas S1PR2 deficiency did not result in B-cell dissemination, suggesting that another Gα13-coupled receptor also regulates GC B cells. Indeed, purinergic receptor P2Y, G-protein coupled 8 (P2RY8) was frequently mutated in human GCB-DLBCL, preventing surface expression of P2RY8. Overexpression of P2RY8 suppressed GC B-cell growth and confined B-cell localization to the GC niche in a Gα13-dependent manner, further supporting a tumor-suppressive role for the Gα13 pathway. Additionally, concomitant loss of Gα13 and overexpression of BCL2, which is often activated by mutations in GCB-DLBCL, were required for GC B-cell survival outside of the GC niche in distant organs including the bone marrow and spleen. Together, these data identify a Gα13-dependent pathway that inhibits the growth and dissemination of GC B cells and suggest inhibition of AKT as a therapeutic strategy in tumors harboring defects in the S1PR2/P2RY8–Gα13–ARHGEF1 pathway.

Muppidi JR, Schmitz R, Green JA, Xiao W, Larsen AB, Braun SE, et al. Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma. Nature 2014 Sep 28 [Epub ahead of print].