Notch2 Controls Non-autonomous Wnt-signalling in Chronic Lymphocytic Leukaemia

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Sep 23

PMID 30242258

Citations 41

Authors

Maurizio Mangolini

Frederik Gotte

Andrew Moore

Tim Ammon

Madlen Oelsner

Gloria Lutzny-Geier

Ludger Klein-Hitpass

James C Williamson

Paul J Lehner

Jan Durig

Michael Mollmann

Livia Raso-Barnett

Katherine Hughes

Antonella Santoro

Simon Mendez-Ferrer

Robert A J Oostendorp

Ursula Zimber-Strobl

Christian Peschel

Daniel J Hodson

Marc Schmidt-Supprian

Ingo Ringshausen

Affiliations

Soon will be listed here.

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.

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