RelB contributes to the survival, migration, and lymphomagenesis of B cells

Hyperactivation of non-canonical NF-kB-signaling is suggested to contribute to lymphomagenesis. This prompted us to study the contribution of the non-canonical NF-kB transcription factor RelB in the initiation and progression of B cell lymphomas. To this end, we generated mice expressing B cell specifically a constitutive active CD40 receptor (LMP1/CD40stopfl) in the presence and absence of RelB. We compared in our analysis the transcriptional profile of splenic B cells from LMP1/CD40//CD19-Cre and LMP1/CD40//RelB-KO//CD19-Cre mice. We found that non-canonical NF-kB signaling results in the overrepresentation of genes involved in B cell survival, activation, migration and cytokine signaling. Under the most significantly regulated genes, were the atypical chemokine receptor Ackr3 and the Cannabinoid receptor Cnr1, which were higher expressed in RelB-proficient B cells compared to RelB-deficient cells. Overexpression of these two genes in CD40-stimulated B cells may explain the enhanced retention of CD40-stimulated B cells in secondary lymphoid organs. This phenotype is strictly dependent on activation of the non-canonical NF-kB signal, as it is absent after inactivation of RelB. Furthermore, we identified under the top-most significantly differentially regulated genes Il-9r and Lilrb4 that were upregulated in Rel-B proficient in comparison to RelB deficient B cells. These two genes have been shown to contribute to B cell proliferation and immunosurveillance, respectively, and thus may have a direct impact on lymphomagenesis. In sum, our results suggest that RelB contributes to lymphomagenesis by regulating genes involved in B cell survival, proliferation, activation and migration.