https://orcid.org/0009-0008-2650-5791
Key Points
AID-imprinted B-cells overexpressing REL leads to both an exacerbated GC reaction and clonal expansion
REL provides a long-term competitive advantage allowing for GC B-cell persistence and continuous recirculation of AID-imprinted B-cells
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) Bcell DLBCL subtype (GCB-DLBCL) for which c-Rel is the pivotal Re/NF-kB subunit. While REL also plays a key role in the GC reaction, its contribution to GCB-DLBCLs remains unclear. 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 model that allows to induce REL in a limited pool of AID-imprinted B-cells after immunization and to differentially stain AID-imprinted B-cells that overexpress REL or not. Dysregulation of REL in AID-imprinted B-cells was associated with nuclear c-Rel overexpression in GCs 14 days after immunization. Dysregulation of REL at the GC B-cell stage promoted GC B-cell expansion, which was associated with both classswitch recombination and plasma cell differentiation. REL overexpression conferred a longterm competitive advantage, allowing GC persistence and continuous recirculation of RELoverexpressing B-cells. Ighv dominance was increased at the mRNA level in RELoverexpressing B-cells and clonal expansion was detected at the DNA level in some cases. Highlighting the role of the immune response, our results demonstrate the advantage conferred by REL in the GC competition and provide evidence that, as an oncogenic event of GC B-cells, its genetic deregulation induces the generation of a long-term pool of lymphoma precursor cells.
