Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11511-6. doi: 10.1073/pnas.1310144110. Epub 2013 Jun 24.
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, genomewide 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 normal mouse bone marrow progenitor 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.
微小 RNA（miRNAs）是一种调节靶基因 mRNAs 的小非编码 RNA，已知其参与癌症的发病机制。急性髓系白血病（AML）是一组具有不同染色体和/或分子异常的异质性造血恶性肿瘤。涉及混合谱系白血病（MLL）基因的染色体易位的 AML 通常与不良预后相关。在本研究中，通过大规模全基因组 miRNA 表达分析，我们表明与正常对照和非 MLL 重排 AML 相比，miR-9（miR-9）是 MLL 重排 AML 中上调最特异的 miRNA。我们证明 miR-9 是 MLL 融合蛋白的直接靶标，并且可以在人类和小鼠造血干/祖细胞中由后者显著上调表达。适当的反义寡核苷酸（antagomiR）耗竭内源性 miR-9 表达可显著抑制人 MLL 重排 AML 细胞的细胞生长/活力并促进细胞凋亡，而当 miR-9 表达被强制时则相反。通过抗 miRNA 海绵阻断内源性 miR-9 功能可显著抑制，而强制表达 miR-9 可显著促进正常小鼠骨髓祖细胞中 MLL 融合诱导的永生化/转化。此外，强制表达 miR-9 可显著促进体内 MLL 融合介导的白血病发生。此外，在一系列白血病样本集中，miR-9 的一组假定靶基因的表达与 miR-9 呈显著负相关，表明它们是 MLL 重排 AML 中 miR-9 的潜在靶标。总之，我们的数据表明 miR-9 是 MLL 重排 AML 中的关键致癌 miRNA，可作为治疗这种恶性疾病的潜在治疗靶点。
