title: Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model.
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.
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Schwarzer
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Nickel
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Godau
authors.affiliation: Julius Wolff Institute and Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: B M
authors.initials: BM
authors.lastname: Willie
authors.affiliation: Julius Wolff Institute and Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: G N
authors.initials: GN
authors.lastname: Duda
authors.affiliation: Institute of Biology and Molecular Biophysics, Humboldt University Berlin, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Schwarzer
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Cirovic
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Leutz
authors.affiliation: Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Manz
authors.affiliation: 1] Centre for Immune Regulation, Institute of Immunology, Oslo University Hospital, Oslo, Norway [2] Jebsen Centre for Research on Influenza Vaccines, University of Oslo, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Bogen
authors.affiliation: 1] Department of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.affiliation: 1] Department of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Department of Internal Medicine II, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Jundt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001847:Bone Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004151:Dipeptides; D051880:Receptors, Notch; C523463:benzyloxycarbonyl-isoleucyl-leucinal