THE ROLE OF NOTCH PATHWAY IN MULTIPLE MYELOMA PROGRESSION: CONTROL OF IL-6 EXPRESSION IN MALIGNANT PLASMA CELLS AND BONE MARROW NICHE

Multiple myeloma (MM) is an incurable hematological tumor characterized by the accumulation of malignant plasma cells (PCs) within the bone marrow (BM). MM cells create a very strictly interaction with the surrounding BM niche that directly supports tumor growth through adhesion molecules and soluble factors, the most important of which is interleukin-6 (IL-6). IL-6 is probably the most important factor for MM cells growth and survival in vivo and it mainly produced by non-neoplastic cells of the BM microenvironment, and at less extent by malignant plasma cells. Recent studies suggest the involvement of NOTCH pathway in the pathogenesis of multiple myeloma. The NOTCH pathway is composed by four isoforms of receptors (NOTCH1-4) and two family of ligands, the Serrate-like ligands (JAGGED1 and 2) and the Delta-like ligands (DLL1/3/4). NOTCH pathway plays an important role in several cellular processes such as proliferation, survival, differentiation and stemness in various tissues and tumors. Regarding MM, the up-regulation of NOTCH signaling is due to the over-expression of both receptors (NOTCH1 and NOTCH2) and ligands (JAGGED1 and JAGGED2): these alterations promote tumor growth, pharmacological resistance, and bone disease. Furthermore, NOTCH pathway plays an important role in the pathological interaction between malignant PCs and the BM niche. This study indicates that there is a correlation between levels of NOTCH signaling members (JAGGED1, NOTCH2, HES5 and HES6) and the malignant progression of the disease. Indeed, NOTCH pathway is involved in multiple myeloma progression since it is able to increase the release of IL-6 produced by BM stromal cells (BMSCs). Our in vitro studies show that NOTCH pathway induces IL-6 gene expression in MM cells as well as in the surrounding BMSCs through the over-expression of JAGGED ligands. The activation of NOTCH pathway in the BMSCs renders these cells able to support tumor cells growth through the production of IL-6. These data are confirmed also by correlation analysis on gene expression profiles of MM patients and immunohistochemical studies. The ability of NOTCH pathway to positively regulate IL-6 in the non-neoplastic cells of BM microenvironment renders this pathway an important mediator of tumor-directed reprogramming of bone marrow niche. These results support the rationale for a NOTCH-direct therapeutic approach that can specifically target JAGGED ligands in order to reduce side effects associated with common NOTCH signaling inhibitor.