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

Oncogene volume 39, pages 2934–2947 (2020)Cite this article

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Abstract

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.

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Fig. 1: BCR-mediated stabilization of β-catenin in primary MCL cells.
Fig. 2: BCR engagement induces β-catenin stabilization and nuclear translocation.
Fig. 3: MCL cells express WNT16 ligands that contribute to β-catenin stabilization.
Fig. 4: β-catenin is involved in non-TCF-dependent transcription.
Fig. 5: β-catenin participates to a complex at NF-κB consensus DNA sequence.

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Acknowledgements

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 ANR11 IDEX00502. We thank Dr C. Leroy for reading the manuscript, Dr L. Guittat for helpful discussion during the experimental work and Dr B. Papp for initiating collaboration with Dr P. Gelebart.

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  1. These authors contributed equally: Gregory Lazarian, Chloe Friedrich

  2. These authors jointly supervised this work: Laura Gardano, Fanny Baran-Marszak

Authors and Affiliations

  1. U978 Institut National de la Santé et de la Recherche Médicale, Bobigny, France

    Gregory Lazarian, Chloe Friedrich, Anne Quinquenel, Julie Tran, Souhail Ouriemmi, Elisabetta Dondi, Antoine Martin, Imane Mihoub, Carole Fleury, Dominique Ledoux, Florence Cymbalista, Nadine Varin-Blank, Laura Gardano & Fanny Baran-Marszak

  2. Université Paris 13, Sorbonne Paris Cité, Labex Inflamex, Bobigny, France

    Gregory Lazarian, Chloe Friedrich, Anne Quinquenel, Julie Tran, Souhail Ouriemmi, Elisabetta Dondi, Antoine Martin, Imane Mihoub, Carole Fleury, Dominique Ledoux, Florence Cymbalista, Nadine Varin-Blank, Laura Gardano & Fanny Baran-Marszak

  3. Service d’Hématologie Biologique, Hôpital Avicenne, Assistance Publique–Hôpitaux de Paris, Bobigny, France

    Gregory Lazarian, Carole Fleury, Florence Cymbalista & Fanny Baran-Marszak

  4. Service d’anatomopathologie, Hôpital Avicenne, Assistance Publique–Hôpitaux de Paris, Bobigny, France

    Antoine Martin

  5. Centre de Recherches en Cancérologie et Immunologie Nantes-Angers, U1232 INSERM, Centre National de la Recherche Scientifique (CNRS) ERL6001, Université de Nantes, Nantes, France

    David Chiron & Céline Bellanger

  6. Department of clinical science, University of Bergen, Bergen, Norway

    Pascal Gélébart & Emmet McCormack

  7. Hématologie, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris, Paris, France

    Catherine Thieblemont

  8. Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia

    Jacek Marzec

  9. Barts Cancer Institute, Queen Mary University of London, London, UK

    John G. Gribben

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Lazarian, G., Friedrich, C., Quinquenel, A. et al. Stabilization of β-catenin upon B-cell receptor signaling promotes NF-kB target genes transcription in mantle cell lymphoma. Oncogene 39, 2934–2947 (2020). https://doi.org/10.1038/s41388-020-1183-x

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