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

In diffuse large B-cell lymphomas (DLBCLs), gains and amplifications of the 2p15-16 region, which always encompass the REL gene, are mostly restricted to the germinal center (GC) B-cell DLBCL subtype (GCB-DLBCL) for which c-Rel is the pivotal Rel/NF-kB subunit. While REL also plays a key role in the GC reaction, its contribution to GCB-DLBCLs remains unclear. At the transcriptomic and phenotypic level, we demonstrate that dysregulation of REL at the GC B-cell stage promotes GC B-cell expansion and favors both class-switch recombination and plasma cell differentiation. Additionally, although REL overexpression was neutral on post-GC memory B-cell differentiation, it did confer a long-term competitive advantage allowing for GC persistence and continuous recirculation of REL-overexpressing B-cells. Functionally, REL enhanced the protection against apoptosis in the early steps of GCB differentiation. Additionally, mRNA IGHV dominance was increased in REL-overexpressing B-cells and clonal expansion could be detected at the DNA level in some cases. Overall design: To understand the role of REL in the very first steps of GCB transformation, i.e when B-cells with deregulated REL are competing with other B-cells during chronic antigenic stimulation, we have created a dual-color mouse that allows to induce REL in a limited pool of AID-imprinted B-cells after immunization and to differentially stain AID-imprinted B-cells cells that overexpress REL or not.