Stabilization of β-catenin upon B-cell receptor signaling promotes NF-kB target genes transcription in mantle cell lymphoma

B-cell receptor (BCR) signaling pathways and interactions with the tumor microenvironment account for mantle cell lymphoma (MCL) cells survival in lymphoid organs. In several MCL cases, the WNT/beta-catenin canonical pathway is activated and beta-catenin accumulates into the nucleus. As both BCR and beta-catenin are important mediators of cell survival and interaction with the microenvironment, we investigated the crosstalk between BCR and WNT/beta-catenin signaling and analyzed their impact on cellular homeostasis as well as their targeting by specific inhibitors. beta-catenin was detected in all leukemic MCL samples and its level of expression rapidly increased upon BCR stimulation. This stabilization was hampered by the BCR-pathway inhibitor Ibrutinib, supporting beta-catenin as an effector of the BCR signaling. In parallel, MCL cells as compared with normal B cells expressed elevated levels of WNT16, a NF-kappa B target gene. Its expression increased further upon BCR stimulation to participate to the stabilization of beta-catenin. Upon BCR stimulation, beta-catenin translocated into the nucleus but did not induce a Wnt-like transcriptional response, i.e., TCF/LEF dependent. beta-catenin rather participated to the regulation of NF-kappa B transcriptional targets, such as IL6, IL8, and IL1. Oligo pull down and chromatin immunoprecipitation experiments demonstrated that beta-catenin is part of a protein complex that binds the NF-kappa B DNA consensus sequence, strengthening the idea of an association between the two proteins. An inhibitor targeting beta-catenin transcriptional interactions hindered both NF-kappa B DNA recruitment and induced primary MCL cells apoptosis. Thus, beta-catenin likely represents another player through which BCR signaling impacts on MCL cell survival.