Abstract
Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-kB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.
| Original language | English |
|---|---|
| Article number | e217 |
| Journal | Blood Cancer Journal |
| Volume | 4 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 06.2014 |
Funding
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, TRR54, TPB6 to FJ and BD), the Deutsche Krebshilfe (108658 to FJ and RM); and the Wilhelm-Sander Stiftung (2011.018.1 to FJ). It was further supported by the Norwegian Cancer Society (BB) and the Multiple Myeloma Research Foundation (BB). We thank Katharina Pardon and Alexander Haake for excellent technical assistance.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
