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.

Genetic alterations in B cell lymphoma subtypes as potential biomarkers for non-invasive diagnosis, prognosis, therapy, and disease monitoring

“…Another study also showed inactivating mutations in components of the GPCR signaling pathway (i.e. GNA13 and RHOA) genes, suggesting that this pathway may be a target of therapy for GNA13 or RHOA-mutated BL cases (O'Hayre et al, 2016).…”

Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapy

“…Mutations in GNA13 have been characterized in both liquid and solid tumors and are present at high frequency in bladder carcinoma. In addition, recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13 in lymphomas, specifically Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL) (71)(72)(73). These mutations in GNA13 as well as in RhoA, a downstream target of G␣ 13 , have been shown to be inhibitory in nature, suggesting a tumorsuppressive role for G␣ 13 and RhoA in Burkitt's lymphoma and DLBCL (71).…”

Opposite RHOA functions within the ATLL category

“…In the report about AITL and BL, G17V and R5Q mutations reduce the guanosine triphosphate (GTP)-binding form of RHOA, and the downstream effector activities like serum response factor transcription and the stress fiber formation significantly decreased. 2,3,8 In addition, it has been shown that the loading of GTP does not occur by G17V mutation. In the case of Y42C mutations in gastric cancer, it has also been shown that the adenosine triphosphate-bound active form has decreased, whereas another report showed selective loss of binding of RHOA to protein kinase N (PKN) effector protein.…”

“…[1][2][3][4][5][6][7][8][9] The disease categories, mutations, and biochemical properties linked to increased and decreased RHOA activity are indicated by red and blue color, respectively. Image of 1A2B 10 created with PyMOL (Schrödinger, LLC).…”