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

Autor: Lazarian G; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France.; Service d'Hématologie Biologique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France., Friedrich C; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Quinquenel A; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Tran J; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Ouriemmi S; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Dondi E; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Martin A; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France.; Service d'anatomopathologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France., Mihoub I; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Chiron D; Centre de Recherches en Cancérologie et Immunologie Nantes-Angers, U1232 INSERM, Centre National de la Recherche Scientifique (CNRS) ERL6001, Université de Nantes, Nantes, France., Bellanger C; Centre de Recherches en Cancérologie et Immunologie Nantes-Angers, U1232 INSERM, Centre National de la Recherche Scientifique (CNRS) ERL6001, Université de Nantes, Nantes, France., Fleury C; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France.; Service d'Hématologie Biologique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France., Gélébart P; Department of clinical science, University of Bergen, Bergen, Norway., McCormack E; Department of clinical science, University of Bergen, Bergen, Norway., Ledoux D; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Thieblemont C; Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France., Marzec J; Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia., Gribben JG; Barts Cancer Institute, Queen Mary University of London, London, UK., Cymbalista F; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France.; Service d'Hématologie Biologique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France., Varin-Blank N; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France. nadine.varin@inserm.fr.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France. nadine.varin@inserm.fr., Gardano L; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France., Baran-Marszak F; U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France. fanny.baran-marszak@aphp.fr.; Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France. fanny.baran-marszak@aphp.fr.; Service d'Hématologie Biologique, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France. fanny.baran-marszak@aphp.fr.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2020 Apr; Vol. 39 (14), pp. 2934-2947. Date of Electronic Publication: 2020 Feb 07.
DOI: 10.1038/s41388-020-1183-x
Abstrakt: 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.
Databáze: MEDLINE
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