Heparan sulfate proteoglycans: key moderators of the interaction of multiple myeloma with the bone marrow niche

Multiple myeloma (MM) is a largely incurable hematological malignancy characterized by a clonal expansion of malignant plasma cell in the bone marrow (BM). The survival and proliferation of MM cells in the BM is highly dependent on signals emanating from the BM microenvironment.
In most MMs, aberrant activation of the Wnt/β-catenin signaling drives proliferation and is associated with disease progression, however, canonical Wnt-pathway activation mutations are rare, indicating that Wnt pathway activation in MM is driven by autocrine and/or paracrine Wnt ligands. In chapter 2, we uncover a previously unknown role for the R-spondin/LGR4 axis in regulating Wnt/β-catenin activation in MM. These results advocate LGR4 as a therapeutic target in MM. High expression of syndecan-1 is a hallmark of plasma cell and its malignant counterpart MM. In chapter 3, we showed that HS chains decorating syndecan-1 bind Wnts and R-spondins to promote aberrant Wnt signaling activation and cell growth in MM. BMSCs secreted CXCL12α plays an important role in MM cell homing and adhesion in the BM niche. However, the role of its alternative splicing isoform CXCL12γ in MM BM microenvironment is still unknown. In chapter 4, we showed that BMSC-derived CXCL12γ functions as a ‘niche chemokine’ that, in conjunction with cell surface HSPGs, plays a unique role in controlling MM cell adhesion, BM retention, and drug resistance. In chapter 5, we reviewed the critical role of HSPGs in the interaction between normal and malignant plasma cells and the BM microenvironment.