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dc.contributor.authorMangolini, Maurizioen
dc.contributor.authorGötte, Frederiken
dc.contributor.authorMoore, Andrewen
dc.contributor.authorAmmon, Timen
dc.contributor.authorOelsner, Madlenen
dc.contributor.authorLutzny-Geier, Gloriaen
dc.contributor.authorKlein-Hitpass, Ludgeren
dc.contributor.authorWilliamson, Jamesen
dc.contributor.authorLehner, Paulen
dc.contributor.authorDürig, Janen
dc.contributor.authorMöllmann, Michaelen
dc.contributor.authorRásó-Barnett, Líviaen
dc.contributor.authorHughes, Katherineen
dc.contributor.authorSantoro, Antonellaen
dc.contributor.authorMéndez-Ferrer, Simónen
dc.contributor.authorOostendorp, Robert AJen
dc.contributor.authorZimber-Strobl, Ursulaen
dc.contributor.authorPeschel, Christianen
dc.contributor.authorHodson, Danielen
dc.contributor.authorSchmidt-Supprian, Marcen
dc.contributor.authorRingshausen, Ingoen
dc.date.accessioned2018-11-08T00:31:16Z
dc.date.available2018-11-08T00:31:16Z
dc.date.issued2018-09-21en
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.mediumElectronicen
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBone Marrow Cellsen
dc.subjectCell Lineen
dc.subjectMesenchymal Stem Cellsen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectReceptor Cross-Talken
dc.subjectbeta Cateninen
dc.subjectReceptor, Notch2en
dc.subjectLeukemia, Lymphocytic, Chronic, B-Cellen
dc.subjectWnt Signaling Pathwayen
dc.subjectCellular Reprogrammingen
dc.titleNotch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2018en
prism.publicationNameNature communicationsen
prism.startingPage3839
prism.volume9en
dc.identifier.doi10.17863/CAM.32135
dcterms.dateAccepted2018-07-31en
rioxxterms.versionofrecord10.1038/s41467-018-06069-5en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-09-21en
dc.contributor.orcidMoore, Andrew [0000-0002-2875-6315]
dc.contributor.orcidLutzny-Geier, Gloria [0000-0002-9648-2635]
dc.contributor.orcidWilliamson, James [0000-0002-2009-189X]
dc.contributor.orcidLehner, Paul [0000-0001-9383-1054]
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.orcidHodson, Daniel [0000-0001-6225-2033]
dc.contributor.orcidRingshausen, Ingo [0000-0002-7247-311X]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMedical Research Council (MR/M008584/1)
pubs.funder-project-idECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (648765)
pubs.funder-project-idNHS Blood and Transplant (NHSBT) ()
pubs.funder-project-idWellcome Trust (101835/Z/13/Z)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idCancer Research UK (17480)


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