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Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model

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Item Type:Article
Title:Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model
Creators Name:Schwarzer, R. and Nickel, N. and Godau, J. and Willie, B.M. and Duda, G.N. and Schwarzer, R. and Cirovic, B. and Leutz, A. and Manz, R. and Bogen, B. and Dörken, B. and Jundt, F.
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-κB 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.
Keywords:Animal Disease Models, Apoptosis, Bone Diseases, Cell Differentiation, Dipeptides, Disease-Free Survival, Enzyme-Linked Immunosorbent Assay, Inbred BALB C Mice, Multiple Myeloma, Notch Receptors, Random Allocation, Signal Transduction, Tumor Cell Line, Xenograft Model Antitumor Assays, Animals, Mice
Source:Blood Cancer Journal
Publisher:Nature Publishing Group
Page Range:e217
Date:13 June 2014
Official Publication:https://doi.org/10.1038/bcj.2014.37
PubMed:View item in PubMed

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