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

Maurizio Mangolini, Frederik Götte, Andrew Moore, Tim Ammon, Madlen Oelsner, Gloria Lutzny-Geier, Ludger Klein-Hitpass, James C. Williamson, Paul J. Lehner, Jan Dürig, Michael Möllmann, Lívia Rásó-Barnett, Katherine Hughes, Antonella Santoro, Simón Méndez-Ferrer, Robert A. J. Oostendorp, Ursula Zimber-Strobl, Christian Peschel, Daniel J. Hodson, Marc Schmidt-Supprian and Ingo Ringshausen ()
Additional contact information
Maurizio Mangolini: University of Cambridge
Frederik Götte: Klinikum rechts der Isar der Technischen Universität München
Andrew Moore: University of Cambridge
Tim Ammon: Klinikum rechts der Isar der Technischen Universität München
Madlen Oelsner: Klinikum rechts der Isar der Technischen Universität München
Gloria Lutzny-Geier: Friedrich-Alexander-University Erlangen-Nürnberg
Ludger Klein-Hitpass: University of Duisburg-Essen
James C. Williamson: University of Cambridge
Paul J. Lehner: University of Cambridge
Jan Dürig: University of Duisburg-Essen
Michael Möllmann: University of Duisburg-Essen
Lívia Rásó-Barnett: Cambridge University Hospitals NHS Foundation Trust
Katherine Hughes: University of Cambridge
Antonella Santoro: University of Cambridge
Simón Méndez-Ferrer: University of Cambridge
Robert A. J. Oostendorp: Klinikum rechts der Isar der Technischen Universität München
Ursula Zimber-Strobl: Research Unit Gene Vectors
Christian Peschel: Klinikum rechts der Isar der Technischen Universität München
Daniel J. Hodson: University of Cambridge
Marc Schmidt-Supprian: Klinikum rechts der Isar der Technischen Universität München
Ingo Ringshausen: University of Cambridge

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06069-5

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