Details

Autor(en) / Beteiligte

• Lazarian, Gregory
• Friedrich, Chloe
• Quinquenel, Anne
• Tran, Julie
• Ouriemmi, Souhail
• Dondi, Elisabetta
• Martin, Antoine
• Mihoub, Imane
• Chiron, David
• Bellanger, Céline
• Fleury, Carole
• Gélébart, Pascal
• McCormack, Emmet
• Ledoux, Dominique
• Thieblemont, Catherine
• Marzec, Jacek
• Gribben, John G
• Cymbalista, Florence
• Varin-Blank, Nadine
• Gardano, Laura
• Baran-Marszak, Fanny

Titel

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

Ist Teil von

• Oncogene, 2020-04, Vol.39 (14), p.2934-2947

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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/β-catenin canonical pathway is activated and β-catenin accumulates into the nucleus. As both BCR and β-catenin are important mediators of cell survival and interaction with the microenvironment, we investigated the crosstalk between BCR and WNT/β-catenin signaling and analyzed their impact on cellular homeostasis as well as their targeting by specific inhibitors. β-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 β-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-κB target gene. Its expression increased further upon BCR stimulation to participate to the stabilization of β-catenin. Upon BCR stimulation, β-catenin translocated into the nucleus but did not induce a Wnt-like transcriptional response, i.e., TCF/LEF dependent. β-catenin rather participated to the regulation of NF-κB transcriptional targets, such as IL6, IL8, and IL1. Oligo pull down and chromatin immunoprecipitation experiments demonstrated that β-catenin is part of a protein complex that binds the NF-κB DNA consensus sequence, strengthening the idea of an association between the two proteins. An inhibitor targeting β-catenin transcriptional interactions hindered both NF-κB DNA recruitment and induced primary MCL cells apoptosis. Thus, β-catenin likely represents another player through which BCR signaling impacts on MCL cell survival.