Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche

Abstract

Multiple myeloma cell growth relies on intrinsic aggressiveness, due to a high karyotypic instability, or on the support from bone marrow (BM) niche.We and other groups have provided evidences that Notch signaling is related to tumor cell growth, pharmacological resistance, localization/recirculation in the BM and bone disease. This work strengthens the rationale for a novel Notch-directed therapy in multiple myeloma based on the inhibition of Jagged ligands.

Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance

“…5D). Additionally, we knocked down Notch1 expression in HS5 cells (N1KD HS5) by using a specific siRNA as previously reported (11) and observed that SDF1α expression significantly decreased in comparison to control HS5 cells ( Fig. 5E).…”

“…Detailed information is in Table S1. Primary BMSCs were isolated as previously reported (11). The Ethical Committee of Milano University approved this study (approval n.8/15).…”

“…To assess if Jagged1 and Jagged2 contribute to MM intrinsic drug resistance, we took advantage of an established knockdown (KD) approach using specific siRNAs for Jagged ligands (11,17) and analyzed MM cell response to three standard-of-care drugs: bortezomib (Bor), melphalan (Melph) and lenalidomide (Len). As reported in experimental timeline in Figure 1A, two HMCLs, OPM2 and U266 cells, were transfected with Jagged1 and Jagged2 (J1/2KD) or the scrambled control (Scr) siRNAs and then were treated with 6 nM Bor or 30 µM Melph or with 15 or 30 µM Len (respectively for U266 and OPM2 cells).…”

“…Notch receptors and ligands have been found to be aberrantly expressed in MM cells (7)(8)(9)(10). We recently demonstrated that Jagged1 and the Notch transcriptional target HES5 are increasingly expressed in MM and in primary plasma cell leukemia (11). Moreover, Jagged1 and Notch1 are overexpressed during progression from the benign monoclonal gammopathy of uncertain significance (MGUS) to MM (12), while Jagged2 overexpression is detected already at the MGUS stage (13) and can be ascribed to aberrant acetylation of its promoter (14) or to altered post-translational processing due to aberrant expression of the ubiquitin ligase Skeletrophin (15).…”

“…Recently, we and other groups pointed out the importance of Jagged ligands in providing MM cells with the ability to shape the surrounding microenvironment, interacting with osteoclast progenitors (17), and promoting a release of BM stromal cell (BMSC) key factors, including IL6, IGF1 and VEGF (11,13).…”