Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.
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Mangolini, M., Götte, F., Moore, A., Ammon, T., Oelsner, M., Lutzny-Geier, G., Klein-Hitpass, L., et al. (2018). Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.. Nature communications, 9 (1), 3839. https://doi.org/10.1038/s41467-018-06069-5
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.
Bone Marrow Cells, Cell Line, Mesenchymal Stem Cells, Animals, Humans, Mice, Receptor Cross-Talk, beta Catenin, Receptor, Notch2, Leukemia, Lymphocytic, Chronic, B-Cell, Wnt Signaling Pathway, Cellular Reprogramming
We would like to express our deepest gratitude to patients who donated blood for research purposes. In particular, we thank Dr Joanna Baxter and her team for enrolling patients in these studies. We are also grateful for the help of Dr Marco Galardini for his bioinformatics support. This work was funded by Cancer Research UK (CRUK; C49940/A17480) and by the Deutsche Forschungsgemeinschaft (DFG, FOR 2033 [projects B3, B6 and B7], I.R. is a senior CRUK fellow
Medical Research Council (MR/M008584/1)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (648765)
NHS Blood and Transplant (NHSBT) ()
Wellcome Trust (101835/Z/13/Z)
Cancer Research UK (17480)
External DOI: https://doi.org/10.1038/s41467-018-06069-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284764
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/