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

Maurizio MangoliniFrederik GötteAndrew MooreTim AmmonMadlen OelsnerGloria Lutzny-GeierLudger Klein-HitpassJames C WilliamsonPaul J LehnerJan DürigMichael MöllmannLívia Rásó-BarnettKatherine HughesAntonella SantoroSimon Mendez-FerrerRobert A J OostendorpUrsula Zimber-StroblChristian PeschelDaniel J HodsonMarc Schmidt-SupprianIngo Ringshausen
Published in: Nature communications (2018)
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.
Keyphrases
  • induced apoptosis
  • cell proliferation
  • cell cycle arrest
  • stem cells
  • endoplasmic reticulum stress
  • oxidative stress
  • transcription factor
  • mesenchymal stem cells
  • copy number
  • long non coding rna
  • cell migration