RATIONALE FOR A NOTCH-DIRECTED THERAPY TO PREVENT MULTIPLE MYELOMA CROSSTALK WITH THE OSTEOCLASTOGENIC NICHE

Multiple myeloma (MM) is an incurable hematological tumor stemming from malignant plasma cells. Similarly to normal plasma cells, MM cells accumulate in the bone marrow (BM) where they establish complex interactions with normal BM stroma, which promote tumor survival and bone disease due to unbalanced bone deposition and resorption. The Notch family of receptors consists of 4 isoforms that, once activated, act as transcription factors. The activation is triggered by membrane-bound ligands (Jagged1-2 and DLL1-3-4). Notch has a key role in the regulation of proliferation, survival, differentiation and stemness in various tissues and tumors. Notch receptors and ligands are deregulated in MM and this signaling system may play a role in the pathogenesis of MM by modulating tumor cell biology, as well as their pathological interactions with the BM niche. Specifically, the myeloma-associated alteration of Notch signaling mainly consists in the aberrant expression of two Notch ligands, Jag1 and Jag2, by tumor cells resulting in Notch signaling activation in both tumor cells and the surrounding cells of the bone niche. Notch mediated signals have been reported to play a role in MM-induced osteoclasts activity and the release of tumor promoting factors by stromal cells. This work unequivocally demonstrates that Notch signaling drives MM cell-induced osteoclastogenesis. The underlying molecular mechanisms is based on: 1) Notch signaling-dependent MM cell ability to promote the release of the osteoclastogenic receptor activator of NF-B ligand (RANKL), 2) Notch2-mediated transcription of osteoclastogenic master genes, such as Tartrate-resistant acid phosphatase (TRAP) and Receptor Activator of Nuclear Factor κ B (RANK), within osteoclast precursors. Notch2 signaling activation, occurring upon RANKL stimulation, results to be necessary for osteoclastogenesis completion, and further boosts the differentiation by promoting an autonomous secretion of RANKL by osteoclasts. Finally, the most crucial finding of this study is that MM-induced osteoclastogenesis could be disrupted by silencing in MM cells two of the Notch ligands, Jag1 and 2,. These results make Jag1 and Jag2 new promising therapeutic targets to hamper MM-associated bone disease and co-morbidities, lacking the toxicity of the currently used drugs which affects the whole Notch pathway.