Wnt signaling in the pathogenesis of multiple myeloma

Multiple myeloma (MM) is a clonal expansion of malignant plasma cells in the bone marrow (BM). Whereas numerous genetic and epigenetic abnormalities have been implicated in MM tumorigenesis, MM cells are highly dependent on a protective BM niche for growth and survival. The aim of the studies described in this thesis was to investigate the reciprocal interaction between multiple myeloma tumor cells and the bone marrow microenvironment. In particular, we focused on mechanisms that facilitate aberrant activation of the canonical Wnt signaling pathway in tumor cells. Oncogenic Wnt signaling typically results from mutations in core pathway components, which cause constitutive, ligand-independent signaling. Whereas most MMs display activation of the canonical Wnt pathway, these cell-intrinsic mutations are rare. Instead, aberrant Wnt signaling activation in MM cells was proposed to be driven by both autocrine Wnt ligands and paracrine Wnts produced in the MM niche. This thesis describes the identification of several genetic and epigenetic abnormalities in MM that sensitize tumor cells to Wnt ligands. Since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors. In addition, the transcriptional effect of hypoxia in MM cells was studied, which identified ADM as an important regulator of angiogenesis in MM.