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- Title
Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.
- Authors
Mangolini, Maurizio; Götte, Frederik; Moore, Andrew; Ammon, Tim; Oelsner, Madlen; Lutzny-Geier, Gloria; Klein-Hitpass, Ludger; Williamson, James C.; Lehner, Paul J.; Dürig, Jan; Möllmann, Michael; Rásó-Barnett, Lívia; Hughes, Katherine; Santoro, Antonella; Méndez-Ferrer, Simón; Oostendorp, Robert A. J.; Zimber-Strobl, Ursula; Peschel, Christian; Hodson, Daniel J.; Schmidt-Supprian, Marc
- 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. The Wnt pathway is one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL) and is activated in only a subset of patients; however, no universal drivers of the disease have been identified. Here the authors show that Notch2 and β-catenin pathways are the main drivers of the pro-survival bidirectional crosstalk between stromal cells and leukemic cells.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-06069-5