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dc.contributor.authorMangolini, Maurizio
dc.contributor.authorGötte, Frederik
dc.contributor.authorMoore, Andrew
dc.contributor.authorAmmon, Tim
dc.contributor.authorOelsner, Madlen
dc.contributor.authorLutzny-Geier, Gloria
dc.contributor.authorKlein-Hitpass, Ludger
dc.contributor.authorWilliamson, James C
dc.contributor.authorLehner, Paul J
dc.contributor.authorDürig, Jan
dc.contributor.authorMöllmann, Michael
dc.contributor.authorRásó-Barnett, Lívia
dc.contributor.authorHughes, Katherine
dc.contributor.authorSantoro, Antonella
dc.contributor.authorMéndez-Ferrer, Simón
dc.contributor.authorOostendorp, Robert AJ
dc.contributor.authorZimber-Strobl, Ursula
dc.contributor.authorPeschel, Christian
dc.contributor.authorHodson, Daniel J
dc.contributor.authorSchmidt-Supprian, Marc
dc.contributor.authorRingshausen, Ingo
dc.date.accessioned2018-11-08T00:31:16Z
dc.date.available2018-11-08T00:31:16Z
dc.date.issued2018-09-21
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284764
dc.description.abstractThe 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.
dc.description.sponsorshipWe 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
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectBone Marrow Cells
dc.subjectCell Line
dc.subjectCellular Reprogramming
dc.subjectHumans
dc.subjectLeukemia, Lymphocytic, Chronic, B-Cell
dc.subjectMesenchymal Stem Cells
dc.subjectMice
dc.subjectReceptor Cross-Talk
dc.subjectReceptor, Notch2
dc.subjectWnt Signaling Pathway
dc.subjectbeta Catenin
dc.titleNotch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameNat Commun
prism.startingPage3839
prism.volume9
dc.identifier.doi10.17863/CAM.32135
dcterms.dateAccepted2018-07-31
rioxxterms.versionofrecord10.1038/s41467-018-06069-5
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09-21
dc.contributor.orcidMoore, Andrew [0000-0002-2875-6315]
dc.contributor.orcidLutzny-Geier, Gloria [0000-0002-9648-2635]
dc.contributor.orcidHughes, Katherine [0000-0002-3331-1249]
dc.contributor.orcidMéndez-Ferrer, Simón [0000-0002-9805-9988]
dc.contributor.orcidOostendorp, Robert AJ [0000-0002-4947-0412]
dc.contributor.orcidRingshausen, Ingo [0000-0002-7247-311X]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/M008584/1)
pubs.funder-project-idEuropean Research Council (648765)
pubs.funder-project-idNHS Blood and Transplant (NHSBT)
pubs.funder-project-idWellcome Trust (101835/Z/13/Z)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idCancer Research UK (17480)
pubs.funder-project-idWellcome Trust (210688/Z/18/Z)
cam.issuedOnline2018-09-21


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International