Proteomics,Multiomics

Dataset Information

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


ABSTRACT: The Wnt-signalling pathway is one of the core de-regulated pathways in chronic lymphocytic leukemia (CLL), activated in a subset of patients by somatic coding mutations. Here we describe an alternative mechanism of Wnt-activation in malignant B cells, mediated by Notch2 activity in mesenchymal stromal cells (MSC) in the tumor microenvironment. We identified that tumor cells specifically induce and activate Notch2 in MSCs. Notch2 orchestrates the expression of target genes essential for the activation of canonical Wnt-signaling in CLL cells. Mechanistically, stromal Notch2 mediates the stabilization of â-catenin by inhibiting the activation of Gsk3-â in malignant B cells. Pharmacological inhibition of the Wnt-pathway mitigates microenvironment-mediated survival of malignant B cells in vitro. Similarly, inhibition of Notch-signaling impaired survival of CLL cells and disease engraftment in a PDX mouse model. Notch2 activation in the tumour microenvironment is a pre-requisite for the GSK3-â dependent activation of the canonical Wnt-signaling in tumor cells.

OTHER RELATED OMICS DATASETS IN: GSE99724GSE99614

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Stromal Cell

DISEASE(S): Chronic Lymphocytic Leukemia

SUBMITTER: James Williamson  

LAB HEAD: Ingo Ringshausen

PROVIDER: PXD010401 | Pride | 2018-09-19

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
IR-MM_CLL-PMP_F-1.mzML Mzml
IR-MM_CLL-PMP_F-1.mzid.gz Mzid
IR-MM_CLL-PMP_F1.raw Raw
IR-MM_CLL-PMP_F10.raw Raw
IR-MM_CLL-PMP_F11.raw Raw
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Publications


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 degradati  ...[more]

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