Stabilization of [beta]-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...
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Veröffentlicht in: | Oncogene 2020-04, Vol.39 (14), p.2934 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0950-9232 |
DOI: | 10.1038/s41388-020-1183-x |