Myeloma interaction with bone marrow stromal cells suppresses ciliogenesis and osteogenic potential in myeloma bone disease
Menée in vitro et à l'aide de modèles murins de myélome multiple, cette étude met en évidence un mécanisme par lequel l'interaction entre les cellules cancéreuses et les cellules stromales de la moelle osseuse supprime la ciliogenèse et l'ostéogenèse
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 Prx1CreCd40lf/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 experimental insights into BMSC dysfunction in MM and suggests that targeting the CD40-SENP1-OFD1 axis could hold promise for MM treatment in clinical settings. Myeloma cell interaction with bone marrow stromal cells leads to impaired ciliogenesis and osteogenesis in myeloma bone disease. Multiple myeloma is frequently accompanied by myeloma bone disease, characterized by osteolytic lesions and low bone density. Bone marrow stromal cells participate in maintaining bone homeostasis; however, the role of BMSCs in myeloma bone disease is not fully characterized. Here, Xie et al. identified a defect in primary cilium formation in BMSCs derived from patients with MM or in BMSCs exposed to direct contact with myeloma cells. Interaction of BMSCs and MM cells through the CD40-CD40L signaling axis led to down-regulation of SENP1, a de-SUMOylation enzyme that modifies OFD1, a key protein required for cilium formation. Overall, they show that the loss of BMSC primary cilia led to less osteogenic potential in vitro and lower bone volume in vivo. Studies in a humanized mouse model suggest that targeting the CD40-CD40L axis may restore the signaling required for ciliogenesis and improve bone density in myeloma. These data provide a foundation for future clinical testing of this strategy. —Molly Ogle
Science Translational Medicine , résumé, 2025