Myeloma interaction with bone marrow stromal cells suppresses ciliogenesis and osteogenic potential in myeloma bone disease

作者：Ying Xie, Ying Xie, Zhaoyun Liu, Qian Li, Tiantian Li, Jing Guo, Meilin Hu, Sun Jiantao, Hongmei Jiang, Jingya Wang, Sheng Wang, Jingjing Wang, Yixuan Wang, Ziyi Peng, Mengqi Wang, Xin Li, Yangyang Xie, Yangyang Xie, Hao Cheng, Linchuang Jia, D Su, Mu Qiao, Jia Song, Xiaozhi Liu, Rong Fu, Zhiqiang Liu · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adq2961 · 被引用次数：6 · 研究领域：Multiple Myeloma Research and Treatments、Bone health and treatments、Ubiquitin and proteasome pathways

Myeloma bone disease, a complication of multiple myeloma (MM), is characterized by impaired osteogenic function of bone marrow stromal cells (BMSCs) and can be an indicator of disease progression. The underlying mechanisms driving BMSC dysfunction are not yet fully understood. This work investigated MM cell interaction with BMSCs, finding that BMSC ciliogenesis is inhibited in the presence of myeloma cells. We demonstrated that direct interaction between myeloma cells and BMSCs through CD40-CD40L led to BMSC down-regulation of sentrin-specific protease 1 (SENP1), a cysteine protease that removes small ubiquitin-like modifier (SUMO) posttranslational modifications. SENP1 down-regulation led to increased SUMOylation of oral-facial-digital syndrome type 1 protein (OFD1), a centriole and centriolar satellite protein, at K931. Increased SUMOylation led to increased OFD1 protein stability and localization at centriolar satellites of primary cilia and decreased ciliogenesis. Consequently, BMSCs lacking primary cilia became desensitized to shear stress stimulation and decreased Hedgehog signaling activation. This cascade of events resulted in inhibited ciliogenesis and osteogenesis in myeloma-BMSC–interacting models, in Prx1 Cre Cd40l f/f mice, and in clinical samples. Treatment with an anti-CD40 neutralizing antibody effectively mitigated bone disruption and tumor burden in the Vk*MYC and SCID (severe combined immunodeficient)–hu mouse models of MM. Overall, our study provides exper...