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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 Gα13/RhoA axis in B cells

Abstract

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 Gα13, in Burkitt’s lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, 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 Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt’s lymphoma and DLBCL.

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Acknowledgements

This study was supported by the National Institute of Dental and Craniofacial Research intramural program at NIH. We thank Maria S Degese for her help with immunohistochemistry. AI was funded by PRESTO from JST. JA was funded by AMED-CREST from AMED. We thank Miho Morikawa for technical assistance with the TGFα shedding assay. RAD and MSL are supported by the Division of Intramural Research, NIAID, NIH. IK is supported by NIH grants R01 GM071872 and R01 AI118985.

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O'Hayre, M., Inoue, A., Kufareva, I. et al. Inactivating mutations in GNA13 and RHOA in Burkitt’s lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Gα13/RhoA axis in B cells. Oncogene 35, 3771–3780 (2016). https://doi.org/10.1038/onc.2015.442

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