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

Author

Listed:
  • Maurizio Mangolini

    (University of Cambridge)

  • Frederik Götte

    (Klinikum rechts der Isar der Technischen Universität München)

  • Andrew Moore

    (University of Cambridge)

  • Tim Ammon

    (Klinikum rechts der Isar der Technischen Universität München)

  • Madlen Oelsner

    (Klinikum rechts der Isar der Technischen Universität München)

  • Gloria Lutzny-Geier

    (Friedrich-Alexander-University Erlangen-Nürnberg)

  • Ludger Klein-Hitpass

    (University of Duisburg-Essen)

  • James C. Williamson

    (University of Cambridge)

  • Paul J. Lehner

    (University of Cambridge)

  • Jan Dürig

    (University of Duisburg-Essen)

  • Michael Möllmann

    (University of Duisburg-Essen)

  • Lívia Rásó-Barnett

    (Cambridge University Hospitals NHS Foundation Trust)

  • Katherine Hughes

    (University of Cambridge)

  • Antonella Santoro

    (University of Cambridge)

  • Simón Méndez-Ferrer

    (University of Cambridge
    NHS Blood and Transplant)

  • Robert A. J. Oostendorp

    (Klinikum rechts der Isar der Technischen Universität München)

  • Ursula Zimber-Strobl

    (Research Unit Gene Vectors)

  • Christian Peschel

    (Klinikum rechts der Isar der Technischen Universität München
    DKFZ)

  • Daniel J. Hodson

    (University of Cambridge)

  • Marc Schmidt-Supprian

    (Klinikum rechts der Isar der Technischen Universität München
    DKFZ)

  • Ingo Ringshausen

    (University of Cambridge)

Abstract

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.

Suggested Citation

  • Maurizio Mangolini & Frederik Götte & Andrew Moore & Tim Ammon & Madlen Oelsner & Gloria Lutzny-Geier & Ludger Klein-Hitpass & James C. Williamson & Paul J. Lehner & Jan Dürig & Michael Möllmann & Lív, 2018. "Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06069-5
    DOI: 10.1038/s41467-018-06069-5
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    Cited by:

    1. Maurizio Mangolini & Alba Maiques-Diaz & Stella Charalampopoulou & Elena Gerhard-Hartmann & Johannes Bloehdorn & Andrew Moore & Giorgia Giachetti & Junyan Lu & Valar Nila Roamio Franklin & Chandra Sek, 2022. "Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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