Anti-Notch treatment prevents Multiple myeloma cell localization to the bone marrow via chemokine system CXCR4/SDF-1

Multiple myeloma (MM) is the second most common hematological malignancy, resulting from a clonal proliferation of malignant plasma cells in the bone marrow (BM) and bone disease. Despite therapeutic advances, MM is still incurable because of chemotherapeutic resistance resulting from MM cells interaction with BM milieu. In addition, in ~80% of patients MM cell localization to the BM results in severe osteolysis, which in turn contributes to tumor progression. CXCR4 and its ligand SDF1α play a primary role in this process and are associated with poor prognosis. To this, SDF-1, expressed by cells in the BM niche, recruits peripheral MM cells to the BM microenvironment by engaging CXCR4 receptor. Notch is family of membrane receptors. Upon binding with ligands on the neighboring cell, Notch is cleaved by the gamma-Secretase complex and the intracellular active portion enters the nucleus where it activates gene transcription. Notch receptors and ligands are deregulated in MM and in the benign monoclonal gammopathy of undetermined significance (MGUS). The Notch pathway activity has been reported to promote MM cells proliferation and survival and increase osteolytic activity. Here we study the interaction between Notch receptors and the CXCR4/SDF1α axis activity in three MM cell lines (OPM2, KMS12, RPMI-8266). Our results confirm that Notch activity stimulates tumor proliferation by reducing the number of cells arrested in G2/M phase, and induce apoptosis resistance. Importantly, we show that Notch controls the expression and function of the CXCR4/SDF1 axis in MM cells and exploits SDF1-mediated proliferation, viability, and MM cells motility to BM. Finally we show that an anti-Notch treatment significantly affects BM invasion by human MM cells in NOD/SCID xenografts indicating that Notch is a rational and promising therapeutic target in this tumor.