Schwarzer R, Nickel N, Godau J, Willie B M, Duda G N, Schwarzer R, Cirovic B, Leutz A, Manz R, Bogen B, Dörken B, Jundt F
Department of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Julius Wolff Institute and Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Blood Cancer J. 2014 Jun 13;4(6):e217. doi: 10.1038/bcj.2014.37.
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.
尽管有证据表明Notch信号失调是多发性骨髓瘤（MM）发病机制的主要调节因子，但其对骨髓瘤骨病的作用仍有待明确。Notch可促进人MM细胞存活并在体外触发人破骨细胞活性。在此，我们发现通过γ-分泌酶抑制剂XII（GSI XII）抑制Notch可诱导具有高Notch活性的小鼠MOPC315.BM骨髓瘤细胞凋亡。GSI XII在体外损害受体激活剂NF-κB配体（RANKL）刺激的RAW264.7细胞的小鼠破骨细胞分化。在小鼠MOPC315.BM骨髓瘤模型中，GSI XII具有强大的抗MM活性并减少溶骨性病变，这可通过骨髓瘤特异性单克隆免疫球蛋白（Ig）-A血清水平降低以及通过高分辨率微型计算机断层扫描对骨结构变化进行定量评估来证明。因此，我们认为通过GSI XII抑制Notch主要通过靶向MM细胞以及可能其微环境中的破骨细胞中的Notch来控制骨髓瘤骨病。我们得出结论，抑制Notch是MM的一种有效治疗策略。
