BMI1 regulates multiple myeloma-associated macrophage’s pro-myeloma functions
Danfeng Zhang, Jingcao Huang, Fangfang Wang, Hong Ding, Yushan Cui, Yan Yang, Juan Xu, Hongmei Luo, Yuhan Gao, Ling Pan, Yu Wu, Yuping Gong, Liping Xie, Zhigang Liu, Ying Qu, Li Zhang, Weiping Liu, Wenyan Zhang, Sha Zhao, Qing Yi, Ting Niu, Yuhuan Zheng
Abstract
Multiple myeloma (MM) is an aggressive malignancy characterized by terminally differentiated plasma cells accumulation in the bone marrow (BM). MM BM exhibits elevated MΦs (macrophages) numbers relative to healthy BM. Current evidence indicates that MM-MΦs (MM-associated macrophages) have pro-myeloma functions, and BM MM-MΦs numbers negatively correlate with patient survival. Here, we found that BMI1, a polycomb-group protein, modulates the pro-myeloma functions of MM-MΦs, which expressed higher BMI1 levels relative to normal MΦs. In the MM tumor microenvironment, hedgehog signaling in MΦs was activated by MM-derived sonic hedgehog, and BMI1 transcription subsequently activated by c-Myc. Relative to wild-type MM-MΦs, BMI1-KO (BMI1 knockout) MM-MΦs from BM cells of BMI1-KO mice exhibited reduced proliferation and suppressed expression of angiogenic factors. Additionally, BMI1-KO MM-MΦs lost their ability to protect MM cells from chemotherapy-induced cell death. In vivo analysis showed that relative to wild-type MM-MΦs, BMI1-KO MM-MΦs lost their pro-myeloma effects. Together, our data show that BMI1 mediates the pro-myeloma functions of MM-MΦs.