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Inactivating mutations in GNA13 and RHOA in Burkitt’s lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the G13/RhoA axis in B cells

O'Hayre, M;Inoue, A;Kufareva, I;Wang, Z;Mikelis, CM;Drummond, RA;Avino, S;Finkel, K;Kalim, KW;DiPasquale, G;Guo, F;Aoki, J;Zheng, Y;Lionakis, MS;Molinolo, AA;Gutkind, JS;

G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein G13, in Burkitt’s lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of G13, RhoA, are also present in Burkitt’s lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type G13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although G13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for G13 and RhoA in Burkitt’s lymphoma and DLBCL.