Loss of Gα13 in B-cells linked to increased lymphoma risk due to dietary glutamine

A recent study published in the journal Nature Immunology, Researchers are investigating the effects of microenvironmental signals on selection in mucosal germinal centers and their role in the development of B-cell lymphomas.

Research: Gα13 regulates nutrient-driven proliferation in mucosal germinal centers. Image credit: Nemes Laszlo / Shutterstock.com

Role of B-cells in mucosal germinal centers

Gut-derived substances modulate germinal centers (GCs) in mucosal tissues and, consequently, are implicated in homeostasis and antigen receptor-driven selection processes. Although GCs are often studied in the context of vaccination or infection, they can also form during normal homeostasis and maintenance of mucosal tissues.

Chronic GCs can develop due to influences of gut microbiome and nutrition. However, it remains unclear what specific dietary factors are involved in mucosal GCs.

Entry of B-cells into GCs can induce deleterious mutations in these immune cells and subsequently increase the risk of certain lymphomas. Diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, is associated with significant genetic heterogeneity arising from the different cells that initiate the cancer process.

The GC of TLBCL originates from a subtype of B-cell-like (GCP) GCPs. Loss of function mutations in G protein subunit alpha 13 (GNA13), which encodes Gα13, are frequently observed in GCB-DLBCL with increased expression of MYC, which plays a key role in both cell growth and division.

Cellular signaling pathways mediated by Gα13 lead to reduced cellular migration, which restricts GCBs to B-cell niches such as bone marrow, secondary lymphoid organs, GCs, and peripheral tissues. Gα13 activity can also inhibit the accumulation of B-cells in GCs, which may be mediated by inhibition of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt).

Although MYC and Gα13 share roles in these processes, the molecular mechanisms involved in the relationship between these two proteins remain unclear. The impact of PI3K/Akt dysregulation on GC accumulation in the absence of Gα13 requires further investigation.

About the study

The researchers examined tumor incidence in mice missing Gα13 in mature B-cells between 10 and 25 months of age. Gα13-deficient mesenteric lymph node (mLN) tumors were obtained from these mice to determine whether deficiency of Gα13 confers an advantage in a competitive setting.

Gnaw13^f/f Mice with GC-specific tamoxifen-inducible fate reporter alleles were hybridized to investigate the increased mutational burden of Gα13 loss due to persistent residence of Gα13-deficient clones in mesenteric lymph node germinal centers.
The researchers also determined whether Gα13-deficiency inhibited PI3K/Akt, with and without enhanced Akt activity.

The role of Gα13-deficiency in GC development and proliferation in mesenteric lymph nodes was investigated. For this purpose, single-cell ribonucleic acid (RNA) sequencing was performed to analyze GCPs isolated from mesenteric lymph nodes (MLNs) or peripheral lymph nodes (PLNs) inoculated in wild-type (WT) or G α13-deficient mice.

The researchers evaluated mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling in Gα13-deficient cells, a reduced cluster of differentiation 4-expressing (CD4+) cells and intestinal lymphoid-derived molecules. They also measured mLN GCB counts and Myc proto-oncogene expression in control and Gα13 knockout bone marrow chimeras. They also investigated the role of glutamine transport proteins in Gα13 depletion in mLN GCBs.

Study results

Gα13-deficient mice developed spontaneous lymphomas in mLN B-cells but not in Beyer’s patches. Furthermore, increased GCB proliferation was observed in intestinal-draining lymph nodes, which subsequently contributed to the development of lymphoma.

Dietary glutamine increased access to intestinal lymphatics in mLN, thereby promoting Gα13-deficient GCB proliferation, which may explain the presence of lymphomas in the intestine. Gα13 deficiency enhanced mLN proliferation by increasing mTORC1 activity and Myc proto-oncogene levels, thereby leading to GC responses.

Gα13-deficient GCBs appear to have a competitive advantage because they can grow successfully in MLNs without T-cell support or the influence of the gut microbiome. Loss of Gα13-mediated inhibitory signaling on mTORC1 signaling and Myc expression may enhance T-cell-independent refueling of Gα13-deficient GCBs, leading to competitive proliferation and clonal stability in the GC state.

Gα13 signaling inhibits mLN GC development, whereas myristoylated Akt (Myr-Akt) expression in mature B-cells promotes cell-intrinsic formation of GCBs in mLNs and, to a lesser extent, in vaccinated pLNs. Myr-Akt gene expression also promoted the development of light zone (LZ) GCB in mesenteric and peripheral lymph nodes.

Mixed chimeras deficient in Gα13 exhibited increased GCB proliferation and reduced pLN proliferation. Diets stimulated the growth of Gα13-deficient GCBs in mLNs. Rapamycin inhibits mTORC1, reducing the competitive ability of Gα13-deficient B cells In laboratory testing mode. Gα13-deficient mLN GCBs exhibited enhanced Myc and proliferation, primarily dependent on mTORC1, Alive.

Impacts

The study shows that oncogenic mutations can circumvent normal homeostasis and promote the proliferation of cancer cells in a tissue-specific way. Main summary appears to regulate GC development, whereas dietary glutamine affects GC selection in mucosal tissue. Mutations in the Gα13 pathway promote malignancy and intestinal tropism in aggressive lymphomas.

Few studies have investigated whether Gα13 deletion leads to enhanced intestinal tropism in human lymphoma. Furthermore, there is a lack of epidemiologic research linking dietary variables to the risk of developing lymphoma. Therefore, further research is needed to investigate the role of diet in the development of lymphomas and whether dietary interventions can be incorporated into the treatment of this disease.