Jagged-directed therapy in multiple myeloma: a new approach to interrupt the crosstalk between the tumor cell and the bone marrow microenvironment

Multiple myeloma (MM) is an incurable hematological tumor stemming from malignant plasma cells. MM cell localization in the bone marrow (BM) niche allows to establish complex interactions with normal stroma, which promote neoplastic cell growth, survival, acquisition of drug resistance and consequent relapse. Localization of MM cells in the BM results also in the development of bone disease, which in turn contributes to tumor progression. In MM cells Notch signaling is aberrantly activated due to increased expression of Notch1-2 receptors and Jagged1-2 ligands. The concomitant aberrant expression of Notch receptors and Jagged ligands results in homotypic and heterotypic Notch activation, which affects both MM cell biology and its pathological interaction with the BM stroma. Our data demonstrate that Notch signaling regulates MM cells homing, proliferation, survival, and resistance to therapy. Moreover, the Notch pathway is crucial for the pathological interaction between MM and BM. Indeed, in MM cells Notch controls the production of the key osteoclastogenic factor RANKL. Overexpressed MM cell-derived Jagged1-2 activate Notch receptors on pre-osteoclasts boosting their differentiation and promoting bone resorption. MM cell-derived Jagged1 and 2 promote also Notch activation in BM stromal cells and stimulate the secretion of anti-apoptotic and growth factors such as IL-6. Finally, we demonstrate that Jagged1-2 silencing inhibits MM cell growth in a murine model of advanced MM. This supports a hypothesis that Jagged targeting may represent a suitable strategy to interrupt the nasty interaction between MM and tumor microenvironment and to prevent the correlated drug resistance and bone disease.