Myeloma formation by RANK signaling and TCL1 in mice highlights implications for human myeloma treatment
Multiple myeloma, characterized by the clonal proliferation of malignant plasma cells in the bone marrow, presents significant challenges in treatment, with only a subset of patients achieving long-term remission. This highlights the urgent need for developing more effective therapeutic strategies. Animal models are crucial in preclinical research, offering invaluable insights into the pathogenesis of myeloma and facilitating innovative new treatments. This study introduces a novel mouse model that closely replicates human multiple myeloma, characterized by rapid disease onset within 7 months and achieving 100% penetrance. Our model accurately mimics critical disease features, including clonal plasma cell expansion that secretes immunoglobulins, leading to kidney failure, anemia, and bone lesions. It also exhibits significant genomic alterations, such as copy number variations and transcriptional profiles, similar to those observed in human myeloma and other murine models. Moreover, the model provides intricate details on the bone marrow niche dynamics and immunosurveillance mechanisms, serving as a comprehensive platform for exploring B cell malignancies and testing new therapeutic options. Crucially, we confirm the expression of RANK in human myeloma cells and the effectiveness of anti-RANKL treatment in xenograft models, shedding light on the observed anti-myeloma effects of denosumab in clinical settings. These contributions offer pivotal insights directly applicable to the treatment of human multiple myeloma. Therefore, our model marks a significant advancement in myeloma research, facilitating an in-depth understanding of the disease's underlying mechanisms and encouraging the development of more effective treatments.