TY - JOUR
T1 - BMI1 regulates multiple myeloma-associated macrophage’s pro-myeloma functions
AU - Zhang, Danfeng
AU - Huang, Jingcao
AU - Wang, Fangfang
AU - Ding, Hong
AU - Cui, Yushan
AU - Yang, Yan
AU - Xu, Juan
AU - Luo, Hongmei
AU - Gao, Yuhan
AU - Pan, Ling
AU - Wu, Yu
AU - Gong, Yuping
AU - Xie, Liping
AU - Liu, Zhigang
AU - Qu, Ying
AU - Zhang, Li
AU - Liu, Weiping
AU - Zhang, Wenyan
AU - Zhao, Sha
AU - Yi, Qing
AU - Niu, Ting
AU - Zheng, Yuhuan
N1 - Funding Information:
This work was supported by grants to Y.Z. from the National Natural Science Foundation of China (No. 81870157 and No. 82070219), Science and Technology Department of Sichuan Province (No. 2019YJ0028), and the Sichuan University Faculty Start Fund; grants to J.H. from the National Natural Science Foundation of China (No. 81800207) and the Health Commission of Sichuan Province (No. 18PJ357), a grant to Y.Q. from Science and Technology Department of Sichuan Province (No. 2018FZ0030); and a grant to Z. L. from Science and Technology Department of Sichuan Province (No. 2019YFS0104).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s41419-021-03748-y
DO - 10.1038/s41419-021-03748-y
M3 - Article
C2 - 33993198
AN - SCOPUS:85106607733
SN - 2041-4889
VL - 12
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 5
M1 - 495
ER -