Notch signaling and multiple myeloma: challenging endogenous and bone marrow-mediated drug resistance

Multiple myeloma (MM) represents the 11% of all hematological malignancies and it is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Although in the last 10 years new drugs such as immunomodulators and proteasome inhibitors increased patients’ survival, MM remains still incurable due to the development of endogenous or BM-mediated drug resistance: therefore it is crucial to find new therapeutic targets. The oncogenic Notch pathway consists in four transmembrane receptors (Notch1-4) and five ligands (Jagged1-2 and Delta-like1, 3, 4). In MM the expression of the ligands Jagged1 and 2 is dysregulated and causes the hyperactivation of Notch receptors in MM cells and in BM stromal cell (BMSC); furthermore several Notch downstream effectors are involved in MM cell growth, survival and proliferation. In this work we evaluated the role of Notch signaling in MM cells intrinsic or BM-mediated drug resistance. Jagged1/2 silencing in MM cells causes a decrease in the expression of anti-apoptotic genes (i.e. Bcl-2, Survivin and ABCC1) finally improving MM cells sensitivity to chemotherapy. Moreover, our results indicate that MM cell-derived Jagged1 and 2 were able to activate the Notch signaling in the surrounding normal cells. Stromal cells, in turn, promote an increase in MM cells anti-apoptotic background, finally reducing their response to chemotherapy. Consistently, Jagged1/2 knock-down was sufficient to restore MM sensibility to standard-of-care therapeutic agents. These evidences suggest that a Jagged1/2-tailored approach could be effective in MM therapy, alone or in combination with commonly used drugs.