Pluto Bioinformatics

GSE125394: Gene expression profiling in RagC T89N germinal center B cells and RagC S74C murine B220+ lymphoma cells

Bulk RNA sequencing

Gene expression by RNAseq in murine germinal centers induced by SRBC in RagC T89N mice (YRT codes) and RNAseq in murine B220+ from VavVPBcl2/RagC S74C and VavVPBcl2/RagC +/+ lymphomas; ; Follicular Lymphoma (FL) is an incurable B cell malignancy derived from germinal center (GC) B cells. The RRAGC gene, encoding a GTPase that links cellular nutrient sufficiency with the activation of mechanistic target of rapamycin complex 1 (mTORC1) is mutated in 15% of FL patients, but its impact in B cell functions and lymphomas is unexplored. Endogenous expression of Rragc mutant variants in B lymphocytes from novel knock-in strains of mice resulted in a partial insensitivity of mTORC1 to nutrient deprivation. A mild, but not a full-blown activation of the nutrient signaling pathway enhanced B cell activation and the GC response, suppressed apoptosis, and accelerated lymphomagenesis. Moreover, murine RRAGC mutant FL showed selective vulnerability to pharmacological inhibition of mTORC1. This moderate increase in nutrient signaling synergized with paracrine cues from the supportive T cell microenvironment that activate mTORC1 via the PI3K-Akt axis to promote B cell activation. Hence, RRAGC mutations sustained experimental GCs and murine and human FL in the presence of decreased T cell support. Moreover, mutations in RRAGC in human FLs are mutually-exclusive with mutations that result in increased abundance of T helper cells, consistent with functional redundancy between those pathways. Taken together, our results support a model in which activating mutations in the nutrient signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control of mTORC1-activating paracrine signals from the T cell microenvironment SOURCE: Kevin Troulé SPANISH NATIONAL CANCER CENTER