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Leukemia. 2019 Feb 15. doi: 10.1038/s41375-019-0404-1. [Epub ahead of print]

Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options.

Author information

1
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2
Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
3
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. s.t.pals@amc.uva.nl.
4
Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands. s.t.pals@amc.uva.nl.

Abstract

Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, 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.

PMID:
30770859
DOI:
10.1038/s41375-019-0404-1

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