Regulatory factor X 7 limits Myc activity during B cell activation and suppresses Myc-dependent lymphomagenesis

Regulatory factor X 7 (RFX7) nonsense mutations have been found in different human B cell malignancies. We therefore set out to study the role of RFX7 in B cell activation and lymphomagenesis. Here we show that RFX7 truncations cause loss-of-function and dominant-negative effects. Moreover, low RFX7 mRNA levels correlate with worse diffuse large B cell lymphoma prognosis. Accordingly, Rfx7 deletion in B cells accelerates pathogenesis in mouse Bcl6- and p53-loss-driven B cell lymphoma models. Rfx7-deficient B cells exhibit increased Myc activity and enhanced germinal center B cell and plasmablast responses. These alterations are reverted by Myc haploinsufficiency, which provides partial protection from nonsymptomatic p53^-/-Rfx7^-/- B cell lymphoma, but does not prevent detrimental Myc deregulation in aggressive disease. Deletion of Aicda, which favors genomic alterations in activated B cells, limits lymphoma development in the p53^-/-Rfx7^-/- double-hit mouse model. These results indicate that Rfx7 represses B cell activation, Myc activity, and Myc- and activation-induced cytidine deaminase (AID)-dependent pro-lymphomagenic processes.