RELderegulation stands as a primary hit for AID-imprinted B-cells along the germinal center competition

Abstract

AbstractIn diffuse large B-cell lymphomas (DLBCLs), gains and amplifications of the 2p15-16 region, which always encompass theRELgene, are mostly restricted to the germinal center (GC) B- cell DLBCL subtype (GCB-DLBCL) for which c-Rel is the pivotal Rel/NF-κB subunit. WhileRELis also known to play a key role in the GC reaction, its contribution to GCB-DLBCL transformation is still unclear. To understand the role ofRELin the very first steps of GCB transformation,i.ewhen B-cells with deregulatedRELare competing with other B-cells during chronic antigenic stimulation, we have created a dual-color mouse that allows to induceRELin a limited pool of AID- imprinted B-cells after immunization and to differentially stain AID-imprinted B-cells cells that overexpressRELor not. Our results demonstrate that dysregulation ofRELat the GC B-cell stage promotes GC B-cell expansion and favors both class-switch recombination and plasma cell differentiation. Additionally, althoughRELoverexpression was neutral on post-GC memory B-cell differentiation, it did confer a long-term competitive advantage allowing for GC persistence and continuous recirculation ofREL-overexpressing B-cells. Functionally,RELenhanced the protection against apoptosis in the early steps of GCB differentiation.REL- overexpressing B-cells can my occasionally transform into in an aggressive B-cell tumor. Highlighting the role of repeated immune responses, our results confirm the role ofRELin the germinal center reaction and provide evidence supporting the fact that genetic deregulation of c-Rel expression is most likely a primary event in the aggressive transformation of GC B-cells.Key points-RELprovides a long-term competitive advantage allowing for GC B-cell persistence and continuous recirculation of AID-imprinted B-cells-AID-imprinted B-cells overexpressingRELcan occasionally transform into aggressive B-cell lymphomasExplanation of the noveltyBy showing in a new dual-color mouse model that dysregulation ofRELin a very limited pool of AID-imprinted B-cells confers a strong long-term competitive advantage in the context of repeated immune responses and may occasionally lead to transformation into an aggressive B- cell lymphoma, we provide for the first time experimental evidence supporting the fact that thatRELis most likely a primary event in the aggressive transformation of germinal center B-cells.