Oncogenic Rag GTPase signalling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR

Abstract

The humoral immune response demands that B cells undergo a sudden anabolic shift and high cellular nutrient levels which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15% of FL samples harbor point, activating mutations in RRAGC, an essential activator of mTORC1 *

The role of metabolic checkpoint regulators in B cell survival and transformation

“…67 Constitutively active RagA renders mTORC1 signaling independent of the presence of amino acids and has been shown to reduce B cell competitiveness in the GC 56 (Figure 2). In contrast, expression of mutant alleles of the gene RagC that drive partial but not complete uncoupling of mTORC1 activity from amino acid dependence has been shown to boost GC expansion 68 (Figure 2). Nutrient and energy levels are also sensed by the LKB1/AMPK pathway, which impinges on mTORC1 activity.…”

Losing control of nutrient sensing in the germinal centre drives lymphomagenesis

“…The same was observed on a Bcl2-transgenic background using VavP-Bcl2 transgenic mice, 10 which also revealed accelerated FL development in vivo. 9 Transcriptional profiling analysis showed enrichment of the mTORC1 signature in RagC- what has previously been observed for mTORC1 hyperactivation. 11 Specifically, strong mTORC1 activation negatively impacted the generation of high-affinity antibodies against the immunizing antigen, which in a competitive setting led to the disappearance of mTORC1-hyperactive versus wild-type GC B-cells over time.…”

“…Experiments performed by Ortega-Molina et al with the mTOR inhibitor rapamycin indicate that such mice, in contrast to mice with Bcl2-translocations only, showed a lower incidence and grade of lymphomas. 9 The observed higher selective sensitivity to mTORC1 inhibition in this mouse model suggests that patients with mutations in the nutrient-signaling pathway may benefit from treatment with mTOR inhibitors.…”

“…5,6 These observations raised two questions: Employing CRISPR/Cas9 genome engineering, Ortega-Molina et al generated two independent Rragc knockin-mouse models that mimic the most frequent human variants of activating RRAGC mutations. 9 In order to assess the presumed aberrant activity of mutated RagC in vitro, amino acids and growth factors that would elicit mTORC1 activation were omitted from the culture medium. Under these conditions, B-cells of the mutant mouse lines showed a greater mTORC1 activity than wild-type mice upon T cellmediated activating signals that during an immune response stimulate the mTORC1 pathway via the PI3K-AKT axis ( Fig.…”

“…These results suggest that RagC-mediated enhancement of mTORC1 activation promotes FL pathogenesis also in humans.In order to gain insights into the pathogenic mechanism of mutated RagC in FL development, the authors determined the biological effects of the mutated gene in the normal cellular counterpart of FL. Upon immunizing RagC-mutated mice with a T celldependent antigen, the authors observed a dramatic increase in the abundance of GC B-cells compared to wild-type controls 9. The difference was even more remarkable in acompetitive reconstitution setting where RagC mutant and wild-type B-cells were assessed in their ability to generate GCs in the same mouse.…”