BMI1 调节多发性骨髓瘤相关巨噬细胞的促骨髓瘤功能。
BMI1 regulates multiple myeloma-associated macrophage's pro-myeloma functions.
机构信息
Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
出版信息
Cell Death Dis. 2021 May 15;12(5):495. doi: 10.1038/s41419-021-03748-y.
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.
多发性骨髓瘤（MM）是一种侵袭性恶性肿瘤，其特征是终末分化的浆细胞在骨髓（BM）中积累。MM BM 中 MΦs（巨噬细胞）的数量相对于健康 BM 升高。目前的证据表明，MM-MΦs（与 MM 相关的巨噬细胞）具有促骨髓瘤功能，BM MM-MΦs 的数量与患者的生存呈负相关。在这里，我们发现 BMI1（一种多梳组蛋白）调节 MM-MΦs 的促骨髓瘤功能，与正常 MΦs 相比，MM-MΦs 表达更高水平的 BMI1。在 MM 肿瘤微环境中，MΦs 中的 hedgehog 信号被 MM 衍生的 sonic hedgehog 激活，随后 c-Myc 激活 BMI1 转录。与野生型 MM-MΦs 相比，来自 BMI1-KO 小鼠 BM 细胞的 BMI1-KO MM-MΦs 表现出增殖减少和血管生成因子表达受到抑制。此外，BMI1-KO MM-MΦs 丧失了保护 MM 细胞免受化疗诱导的细胞死亡的能力。体内分析表明，与野生型 MM-MΦs 相比，BMI1-KO MM-MΦs 丧失了促骨髓瘤作用。总之，我们的数据表明 BMI1 介导了 MM-MΦs 的促骨髓瘤功能。
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