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

Autor: Anne Quinquenel, Julie Tran, Pascal Gelebart, Nadine Varin-Blank, Laura Gardano, Florence Cymbalista, Dominique Ledoux, Carole Fleury, Souhail Ouriemmi, Catherine Thieblemont, Emmet McCormack, David Chiron, Imane Mihoub, Chloé Friedrich, Fanny Baran-Marszak, Celine Bellanger, Antoine Martin, Elisabetta Dondi, Gregory Lazarian, Jacek Marzec, John G. Gribben
Přispěvatelé: Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Service d'hématologie biologique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Service de Pathologie [Hôpital Avicenne - APHP], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), University of Bergen (UiB), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), University of Melbourne, Queen Mary University of London (QMUL), CF was the recipient of a 'Année Recherche' support from APHP. AQ was the recipient of a Jansen fellowship. This project was funded by a 'Bonus Qualité Recherche' grant from University Paris 13 and benefited from the financial support of INSERM, University Paris 13 and the Labex INFLAMEX, contract ANR-11-IDEX-00502., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Bernardo, Elizabeth, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Cité (UPCité), Signalisation, Microenvironnement et Hémopathies Lymphoïdes B (SIMHEL), Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord-Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Oncogene
Oncogene, Nature Publishing Group, 2020, 39 (14), pp.2934-2947. ⟨10.1038/s41388-020-1183-x⟩
Oncogene, 2020, 39 (14), pp.2934-2947. ⟨10.1038/s41388-020-1183-x⟩
ISSN: 0950-9232
1476-5594
DOI: 10.1038/s41388-020-1183-x⟩
Popis: International audience; 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: OpenAIRE
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