Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy

Stromal cells are essential components of the bone marrow (BM) microenvironment that regulate and support the survivalof different tumors, including chronic lymphocytic leukemia (CLL). In this study, we investigated the role of Notch signalingin the promotion of survival and chemoresistance of human CLL cells in coculture with human BM-mesenchymal stromalcells (hBM-MSCs) of both autologous and allogeneic origin. The presence of BM-MSCs rescued CLL cells from apoptosis bothspontaneously and following induction with various drugs, including Fludarabine, Cyclophosphamide, Bendamustine, Prednisoneand Hydrocortisone. The treatment with a combination of anti-Notch-1, Notch-2 and Notch-4 antibodies or g-secretase inhibitor XII (GSI XII) reverted this protective effect by day 3, even in presence of the above-mentioned drugs. Overall, our findings show that stromal cell-mediated Notch-1, Notch-2 and Notch-4 signaling has a role in CLL survival and resistance to chemotherapy. Therefore, its blocking could be an additional tool to overcome drug resistance and improve the therapeutic strategies for CLL.