miR-10a is aberrantly overexpressed in Nucleophosmin1 mutated acute myeloid leukaemia and its suppression induces cell death.
miR-10a is aberrantly overexpressed in Nucleophosmin1 mutated acute myeloid leukaemia and its suppression induces cell death.
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DOI：
10.1186/1476-4598-11-8
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发表时间：
2012-02-20
期刊：
影响因子：
37.3
通讯作者：
Ma DD
中科院分区：
文献类型：
--
作者：
Bryant A;Palma CA;Jayaswal V;Yang YW;Lutherborrow M;Ma DD
急性髓性白血病（AML）伴核磷蛋白-1（NPM 1）突变是AML的一种主要亚型。NPM 1突变诱导骨髓增生性疾病，但有证据表明，其他损伤是AML发展所必需的。我们利用microRNA微阵列和功能测定来确定microRNA失调是否可能参与NPM 1突变（NPM 1 mut）-AML的发病机制。我们使用基于严格锁核酸（LNA）的microRNA微阵列平台来分析正常核型AML患者的骨髓样本。一组五种microRNA根据他们的NPM 1突变状态对AML患者进行二分。与NPM 1野生型AML相比，NPM 1 mut-AML中miR-10a、let-7 b和let-7 c显著过表达，而miR-130 a和miR-335表达不足。其中，miR-10a在NPM 1 mut-AML与NPM 1野生型AML中差异表达最大（通过qRT-PCR证实高出> 10倍）。为了研究miR-10a的功能，使用OCI-AML 3细胞系，其是唯一可商购的携带NPM 1 mut的细胞系。首次证明OCI-AML 3细胞具有与原代NPM 1 mut-AML患者样品相似的高miR-10a表达。在这些细胞中，miRCURY LNA抑制剂（miRCURY LNA Inhibitor）（miRCURY LNA Inhibitor）（miRCURY LNA Inhibitor）抑制miR-10 a表达导致MTS、细胞周期和膜联蛋白-V测定法评估的细胞死亡增加，克隆形成能力降低，表明参与白血病细胞存活。对miR-10a的生物信息学预测的靶点进行计算机过滤，鉴定了许多在造血、细胞生长和凋亡中具有注释功能的潜在mRNA靶点。Lucferase报告基因分析证实了许多这些推定的肿瘤发生基因是miR-10a可抑制的，包括KLF 4和RB 1CC 1。这为miR-10a在NPM 1 mut-AML中的致病作用提供了潜在机制。这项研究首次提供了miR-10a在NPM 1 mut-AML中的促生存作用的体外证据，它可能有助于NPM 1 mut-AML的发病机制，并确定了推定的致肿瘤靶点。
Acute myeloid leukaemia (AML) with nucleophosmin-1 (NPM1) mutation is a major subtype of AML. The NPM1 mutation induces a myeloproliferative disorder, but evidence indicates that other insults are necessary for the development of AML. We utilised microRNA microarrays and functional assays to determine if microRNA dysregulation could be involved in the pathogenesis of in NPM1 mutated (NPM1mut)-AML. We used a stringent locked nucleic acid (LNA) based microRNA microarray platform to profile bone marrow samples of patients with normal karyotype AML. A panel of five microRNAs dichotomised AML patients according to their NPM1 mutational status. miR-10a, let-7b and let-7c were significantly over-expressed, while miR-130a and miR-335 were under-expressed in NPM1mut-AML when compared to NPM1wildtype-AML. Of these, miR-10a is the most differentially expressed in NPM1mut-AML versus NPM1wildtype-AML (> 10 fold higher as confirmed by qRT-PCR). To investigate the functions of miR-10a, the OCI-AML3 cell line was utilised, which is the only commercially available cell line bearing NPM1mut. OCI-AML3 cells were firstly demonstrated to have a similarly high miR-10a expression to primary NPM1mut-AML patient samples. Inhibition of miR-10a expression by miRCURY LNA Inhibitors (Exiqon) in these cells resulted in increased cell death as assessed by MTS, cell cycle and Annexin-V assays and reduced clonogenic capacity, indicative of an involvement in leukaemic cell survival. In silico filtering of bioinformatically predicted targets of miR-10a identified a number of potential mRNA targets with annotated functions in haematopoiesis, cell growth and apoptosis. Lucferase reporter assays confirmed a number of these putative tumorogenic genes that are miR-10a suppressible including KLF4 and RB1CC1. This provides a potential mechanism for the pathogenic role of miR-10a in NPM1mut-AML. This study provides, for the first time, in vitro evidence of a pro-survival role of miR-10a in NPM1mut-AML, that it may contribute to the pathogenesis of NPM1mut-AML and identifies putative tumorogenic targets.
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影响因子：
158.5
作者：
Falini, B;Mecucci, C;Martelli, MF
通讯作者：
Martelli, MF
影响因子：
5.7
作者：
Chai, Guolin;Liu, Ning;Yu, Xijie
通讯作者：
Yu, Xijie
影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Debernardi, S;Lillington, DM;Young, BD
通讯作者：
Young, BD