miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia
miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia
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DOI：
10.1073/pnas.1310144110
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发表时间：
2013-07-09
影响因子：
11.1
通讯作者：
Chen, Jianjun
中科院分区：
文献类型：
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作者：
Chen, Ping;Price, Colles;Chen, Jianjun
微RNA（microRNAs，miRNAs）是一种调节靶基因mRNA的非编码小RNA，与肿瘤的发生、发展密切相关。急性髓系白血病（acute myeloid leukemia，AML）是一组具有多种染色体和/或分子异常的异质性造血系统恶性肿瘤。AML伴有涉及混合系白血病（MLL）基因的染色体易位通常与生存率低相关。在本研究中，通过大规模的全基因组miRNA表达测定，我们发现microRNA-9（miR-9）是MLL重排AML中与正常对照和非MLL重排AML相比最特异性上调的miRNA。我们证明了miR-9是MLL融合蛋白的直接靶点，并且可以在人类和小鼠造血干/祖细胞中通过后者显著上调表达。通过适当的miR-9抑制剂消耗内源性miR-9表达可以显著抑制人ML重排AML细胞的细胞生长/活力并促进细胞凋亡，而当miR-9的表达被强制时则相反。在体外实验中，用抗miRNA海绵阻断内源性miR-9功能可显著抑制MLL融合诱导的正常小鼠骨髓祖细胞永生化/转化，而强制表达miR-9则可显著促进MLL融合诱导的正常小鼠骨髓祖细胞永生化/转化。此外，miR-9的强制表达可显著促进MLL融合介导的体内白血病发生。此外，一组推定的miR-9靶基因在一系列白血病样本集中表现出与miR-9的表达显著负相关，表明它们是ML重排AML中miR-9的潜在靶基因。总的来说，我们的数据表明miR-9是ML重排AML中的关键oncomiR，并且可以作为治疗这种令人沮丧的疾病的潜在治疗靶点。
MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. In the present study, through a large-scale, genome-wide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL-rearranged AML compared with both normal control and non-MLL-rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL-rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti-miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion-induced immortalization/transformation of normalmouse bone marrowprogenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion-mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL-rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL-rearranged AML and can serve as a potential therapeutic target to treat this dismal disease.