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

In a recent study published in the journal Nature Immunology, researchers investigate the effects of microenvironment signals on selection in mucosal germinal centers and their role in the development of B-cell lymphomas.

Study: Gα13 restricts nutrient-driven proliferation in mucosal germinal centers. Image Credit: Nemes Laszlo / Shutterstock.com

The role of B-cells in mucosal germinal centers

Gut-derived substances modulate germinal centers (GCs) in mucosal tissues and, as a result, are implicated in homeostasis and antigen receptor-driven selection processes. Although GCs are often investigated in the context of vaccination or infection, they can also develop during the regular homeostasis and maintenance of mucosal tissues.

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

The entrance of B-cells into GCs can induce harmful 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 different cells that initiate the cancerous process.

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

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

Although MYC and Gα13 have shared 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 also requires additional investigation.

About the study

The researchers studied 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 the lack of Gα13 provided an advantage in a competitive setting.

Gna13^f/f mice were crossbred with those possessing GC-specific tamoxifen-inducible fate reporter alleles to investigate whether Gα13 loss resulted in an increased mutational burden due to the sustained residence of Gα13-deficient clones in the mesenteric lymph node germinal centers.
The researchers also determined whether Gα13-deficiency, with and without enhanced Akt activity, inhibits PI3K/Akt.

The role of Gα13-deficiency in GC growth and proliferation in mesenteric lymph nodes was also investigated. To this end, single-cell ribonucleic acid (RNA) sequencing was performed to analyze GCBs isolated from mesenteric lymph nodes (mLNs) or vaccinated peripheral lymph nodes (pLNs) in wild-type (WT) or Gα13-deficient mice.

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

Study findings

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

Dietary glutamine increased access to gut lymphatics in mLN, thereby promoting Gα13-deficient GCB proliferation, which may explain the presence of lymphomas in the gut. 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, as they can successfully grow in mLNs without T-cell support or influence from 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, thus leading to competitive proliferation and clonal persistence in the GC state.

Gα13 signaling inhibits mLN GC growth, whereas myristoylated Akt (Myr-Akt) expression in mature B-cells promotes the cell-intrinsic formation of GCBs in mLNs and, to a lesser extent, among vaccinated pLNs. Myr-Akt genetic 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. Dietary foods promoted the development of Gα13-lacking GCBs in mLNs. Rapamycin inhibited mTORC1, decreasing the competitive advantage of Gα13-deficient B cells in vitro. Gα13-deficient mLN GCBs exhibited enhanced Myc and proliferation, primarily dependent on mTORC1, in vivo.

Implications

The study shows that oncogenic mutations can circumvent normal homeostasis and promote the proliferation of cancer cells in a tissue-specific way. Niche constriction appears to control GC development, whereas dietary glutamine influences GC selection in mucosal tissues. Mutations in the Gα13 pathway enhance malignancy and gut tropism in aggressive lymphomas.

Few studies have investigated whether Gα13 deletion leads to enhanced gut tropism in human lymphoma. Furthermore, there remains a lack of epidemiological research linking dietary variables to the risk of developing lymphoma. Thus, further research is needed to investigate the role of diet in the development of lymphomas and whether dietary interventions could be incorporated into treating this disease.