AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB
AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB
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DOI：
10.1126/scisignal.aaf2797
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发表时间：
2016-09-06
影响因子：
7.3
通讯作者：
Kurre, Peter
中科院分区：
文献类型：
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作者：
Hornick, Noah I.;Doron, Ben;Kurre, Peter
外泌体是肿瘤微环境的旁分泌调节剂，含有复杂的货物。我们之前报道了急性髓性白血病（AML）细胞释放的外泌体可以通过基质对生态位保留因子的重编程间接抑制残余造血干细胞和祖细胞（HSPC）功能。我们发现造血功能的全身性丧失也部分是AML外泌体导向的microRNA （miRNA）转运到HSPCs的结果。从培养的AML中分离的外泌体或从携带AML异种移植物的小鼠的血浆中分离的miR-150和miR-155富集。通过miR-150和mir -155介导的抑制编码c-MYB（一种参与HSPC分化和增殖的转录因子）转录本的翻译，HSPC与这些外泌体中的任何一种共培养表现出受损的克隆原性。为了发现更多的miRNA靶点，我们采用减毒rna诱导沉默复合体（RISC）陷阱共免疫沉淀的方法捕获了miR-155及其靶转录物，然后进行了高通量测序。该方法鉴定了已知和以前未知的miR-155靶转录本。将miR-155靶标与来自蛋白质相互作用数据库STRING的信息整合，揭示了受AML外泌体衍生的miRNA间接影响的蛋白质。我们的研究结果表明，AML外泌体对HSPCs的直接影响，通过一种与基质无关的机制，损害了造血功能。此外，将miRNA靶点数据与蛋白-蛋白相互作用数据相结合可能是一种广泛适用的策略，可用于定义肿瘤微环境中外泌体介导的调节分子运输的影响。
Exosomes are paracrine regulators of the tumor microenvironment and contain complex cargo. We previously reported that exosomes released from acute myeloid leukemia (AML) cells can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors. We found that the systemic loss of hematopoietic function is also in part a consequence of AML exosome-directed microRNA (miRNA) trafficking to HSPCs. Exosomes isolated from cultured AML or the plasma from mice bearing AML xenografts exhibited enrichment of miR-150 and miR-155. HSPCs cocultured with either of these exosomes exhibited impaired clonogenicity, through the miR-150- and miR-155-mediated suppression of the translation of transcripts encoding c-MYB, a transcription factor involved in HSPC differentiation and proliferation. To discover additional miRNA targets, we captured miR-155 and its target transcripts by coimmunoprecipitation with an attenuated RNA-induced silencing complex (RISC)-trap, followed by high-throughput sequencing. This approach identified known and previously unknown miR-155 target transcripts. Integration of the miR-155 targets with information from the protein interaction database STRING revealed proteins indirectly affected by AML exosome-derived miRNA. Our findings indicate a direct effect of AML exosomes on HSPCs that, through a stroma-independent mechanism, compromises hematopoiesis. Furthermore, combining miRNA target data with protein-protein interaction data may be a broadly applicable strategy to define the effects of exosome-mediated trafficking of regulatory molecules within the tumor microenvironment.