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

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.

Bone Marrow Stromal Cells Drive Key Hallmarks of B Cell Malignancies

“…In brief, it was shown that the central regulator of WNT signalling, β -catenin, was stabilised by direct cell contact to BMSCs. The underlying mechanisms involve phosphorylation of GSK3-β and transcriptional up-regulation of N-Cadherin, thereby allowing β-catenin to accumulate and to co-activate transcription in the nucleus [18]. Notably similar results were obtained by other groups in acute lymphoblastic leukaemia, demonstrating that microenvironment-mediated stabilisation of β-catenin also increases drug resistance [20,21].…”

“…Recent data from our group have shown that, in a contact dependent manner, leukemic cells specifically activate NOTCH2 signalling in BMSCs with an associated loss of NOTCH1. This activation leads to the production of soluble factors, such as C1q, which has been shown to promote CLL cell survival, similar to effects observed on metastatic lesions of solid tumours [18,71]…”

“…All of them have beneficial effects for the survival of malignant cells [69,70]. Similar to myeloma cells, CLL cells also express NOTCH ligands [18,26,66]. Recent data from our group have shown that, in a contact dependent manner, leukemic cells specifically activate NOTCH2 signalling in BMSCs with an associated loss of NOTCH1.…”

“…In order to understand the genetic basis for this anti-apoptotic response, we had assessed gene expression changes induced in primary Chronic Lymphocytic Leukaemia (CLL) cells by direct contact to BMSCs. Though controlling this experiment is difficult since primary cells in culture are prone to die in the absence of stromal cells, we identified hundreds of genes activated in response to cell contact, with functions in signalling, cell adhesion and metabolic pathways [18]. Alignment of these data to the gene expression data from primary 'bone marrow-derived' CLL cells, published by the Wiestner group [19], identified a 31% overlap between their and our data (unpublished comparison), indicating that co-culture in vitro systems using BMSCs and primary tumour cells sufficiently recapitulate important cell-cell interactions found in patients.…”

Complement in Metastasis: A Comp in the Camp

“…In malignant pleural mesothelioma, C1q binds to hyaluronic acid in the tumor microenvironment and enhances tumor proliferation (73). C1q secreted by mesenchymal stromal cells mediates the activation of β-catenin in chronic lymphocytic leukemia and enhances malignant progression (74). On the other hand, properdin, a positive regulator of complement activity, induces endoplasmic reticulum-stress response and exerts a tumor suppressive role in breast cancer (75).…”