Multiple myeloma-associated drug resistance : targeting the Notch pathway

Multiple myeloma (MM) represents 11% of hematological malignancies and is caused by the accumulation of malignant plasma cells in the bone marrow (BM). Although treatments with new drugs, such as immunomodulators and proteasome inhibitors, are increasing patients’ survival, MM is still incurable due to the development of endogenous or BM mediated drug resistance. Therefore it is important to find new therapeutic targets. The dysregulated expression of two Notch ligands, Jagged1 and 2, causes the hyperactivation of the Notch signaling both in MM cells and in bone marrow stromal cell (BMSC). The aim of this study was to investigate the role of Notch signaling in endogenous and BMSC-induced drug resistance in MM. At this purpose, we silenced two Notch ligands, Jagged1 and 2, in the MM cell lines OPM-2 and U266. Jagged1/2 silencing causes a reduction in the expression of anti-apoptotic genes, i.e. SDF-1alpha, Bcl-XL, Bcl-2, Survivin and ABCC1. In accordance, MM cells with reduced levels of Jagged1 and 2 showed an increased sensitivity to different drugs commonly used in MM therapy such as Bortezomib, Mitoxantrone and Melphalan. In addition, Jagged1/2 knockdown affects the pathological interaction between MM and BMSCs resulting in the activation of Notch signaling in both cell types. Indeed, when co-cultured with human BMSCs, MM cells displayed an higher level of drug resistance due to: 1) an increased expression of anti-apoptotic genes in MM cells, i.e. Bcl-XL, Bcl-2, Survivin and ABCC1; 2) the BMSC-mediated release of soluble factors, i.e. SDF-1alpha and VEGF, relevant for MM cell growth and survival. Jagged1 and 2 silencing in MM cells could reverse all these effects. These in vitro results were confirmed in co-culture experiments performed with primary human CD138+ multiple myeloma cells and BMSCs isolated from patient’s bone marrow aspirates. The evidence that Jagged-1/2 silencing affects endogenous and BMSC-induced drug resistance in MM cells supports the use of a Jagged-targeted approach in MM therapy alone or in a combination with standard of care drugs.