Dll1/Notch activation accelerates multiple myeloma disease development by promoting CD138+ MM cell proliferation

Relapse often occurs after multiple myeloma patients' recovery from chemotherapy. Notch receptors and ligands are presented in MM cells and in bone marrow stromal cells. Here we investigated the role of Dll1/Notch pathway in MM clonogenic growth and in vivo engraftment as well as the role in MM bulk cell proliferation and apoptosis. Dll1/Notch interaction could promote MM clonogenic growth while the Notch inhibitor, DAPT, could strongly inhibit MM colony-forming ability in vitro. Furthermore, DAPT only had a limited inhibition on MM bulk cell growth, mostly by suppressing MM cell proliferation rather than induction of apoptosis. In vivo experiments demonstrated that Notch activation could accelerate MM development. Blocking Notch signaling with DAPT, however, could significantly suppress MM initiation and delayed the in vivo engraftment. Furthermore, Dll1/Notch interaction promotes MM-cell proliferation predominantly in CD138+ MM cells by reducing the expression of p21 and p27, thus accelerating MM cell cycling.