miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding
miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding
复制标题
miR-34c-5p 通过选择性 RAB27B 靶向抑制外泌体脱落诱导衰老，从而促进急性髓系白血病干细胞的根除
DOI：
10.1038/s41375-018-0015-2
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发表时间：
2018-05-01
期刊：
影响因子：
11.4
通讯作者：
Liu, Lingbo
中科院分区：
文献类型：
--
作者：
Peng, Danyue;Wang, Huifang;Liu, Lingbo
白血病干细胞（LSCs）是急性髓系白血病（AML）化疗耐药和复发的原因。在这里，我们发现，与正常造血干细胞（hsc）相比，在AML（非急性早幼粒细胞白血病，非apl）干细胞中，衰老调节网络中心的microRNA miR-34c-5p显著下调。LSCs中miR-34c-5p的低表达与AML患者预后不良和治疗反应差密切相关。在免疫缺陷小鼠中，miR-34c-5p表达升高可诱导LSCs体外衰老，阻止白血病的发生，促进LSCs的清除。在机制上，miR-34-5p的强制表达通过p53- p21cip1 -Cyclin依赖性激酶(CDK)/Cyclin或p53非依赖性CDK/Cyclin途径诱导LSCs衰老。外泌体介导的miR-34c-5p转移是LSCs中miR-34c-5p缺失的原因之一。此外，miR-34c-5p可以通过RAB27B（一种促进外泌体脱落的分子）的正反馈回路抑制外泌体介导的转移，从而增加其细胞内水平。总体而言，本研究建立了一种治疗AML患者的新策略，通过增加miR-34c-5p表达来靶向LSCs重新启动衰老。这种mirna介导的肿瘤干细胞衰老在其他恶性肿瘤中也具有重要的治疗价值。
Leukemia stem cells (LSCs) are responsible for acute myeloid leukemia (AML) chemotherapy resistance and relapse. Here, we discovered that miR-34c-5p, a microRNA central to the senescence regulation network, was significantly down-regulated in AML (non-acute promyelocytic leukemia, non-APL) stem cells compared to that in normal hematopoietic stem cells (HSCs). The lower expression of miR-34c-5p in LSCs was closely correlated to the adverse prognosis and poor responses to therapy of AML patients. Increased miR-34c-5p expression induced LSCs senescence ex vivo, prevented leukemia development and promoted the eradication of LSCs in immune deficient mice. Mechanistically, forced expression of miR-34-5p induced senescence in LSCs through p53-p21Cip1-Cyclin-dependent kinase (CDK)/Cyclin or p53-independent CDK/Cyclin pathways. Exosome-mediated transfer of miR-34c-5p was one of the reasons for miR-34c-5p deficiency in LSCs. Furthermore, miR-34c-5p could increase its intracellular level by inhibiting exosome-mediated transfer via a positive feedback loop through RAB27B, a molecule that promotes exosome shedding. Overall, this study establishes a new strategy for treatment of AML patients by targeting LSCs to reinitiate senescence via increased miR-34c-5p expression. This miRNA-mediated tumor stem cell senescence could also have important therapeutic value in other malignancies.