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Mangolini, M.* ; Götte, F.* ; Moore, A.* ; Ammon, T.* ; Oelsner, M.* ; Lutzny-Geier, G.* ; Klein-Hitpass, L.* ; Williamson, J.C.* ; Lehner, P.J.* ; Dürig, J.* ; Möllmann, M.* ; Rásó-Barnett, L.* ; Hughes, K.* ; Santoro, A.* ; Méndez-Ferrer, S.* ; Oostendorp, R.A.J.* ; Zimber-Strobl, U. ; Peschel, C.* ; Hodson, D.J.* ; Schmidt-Supprian, M.* ; Ringshausen, I.*

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

Nat. Commun. 9:3839 (2018)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 9, Issue: 1, Pages: , Article Number: 3839 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed