Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia

Mangolini M, Goette F, Moore A, Ammon T, Oelsner M, Lutzny-Geier G, Klein-Hitpass L, Williamson JC, Lehner PJ, Duerig J, Moellmann M, Raso-Barnett L, Hughes K, Santoro A, Mendez-Ferrer S, Oostendorp RAJ, Zimber-Strobl U, Peschel C, Hodson DJ, Schmidt-Supprian M, Ringshausen I (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 9

Journal Issue: 1

DOI: 10.1038/s41467-018-06069-5

Abstract

The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-β mediated degradation of β-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises β-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells.

Involved external institutions

Technische Universität München (TUM) DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE) University of Cambridge GB United Kingdom (GB) Cambridge University Hospital GB United Kingdom (GB) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE)

How to cite

APA:

Mangolini, M., Goette, F., Moore, A., Ammon, T., Oelsner, M., Lutzny-Geier, G.,... Ringshausen, I. (2018). Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-06069-5

MLA:

Mangolini, Maurizio, et al. "Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia." Nature Communications 9.1 (2018).

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