title: 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.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: O'Hayre
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.|PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Kufareva
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Mikelis
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Drummond
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.|Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (Cs), Italy.
authors.forename: S
authors.initials: S
authors.lastname: Avino
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Finkel
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Kalim
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: DiPasquale
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: F
authors.initials: F
authors.lastname: Guo
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.|Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), AMED, Chiyoda-ku, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Lionakis
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.|Department of Pharmacology, UC San Diego Moores Cancer Center, La Jolla, CA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004285:Dogs; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein