Musashi-2 Silencing Exerts Potent Activity against Acute Myeloid Leukemia and Enhances Chemosensitivity to Daunorubicin.
Musashi-2 Silencing Exerts Potent Activity against Acute Myeloid Leukemia and Enhances Chemosensitivity to Daunorubicin.
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Musashi-2 沉默对急性髓系白血病具有有效活性，并增强对柔红霉素的化学敏感性
DOI：
10.1371/journal.pone.0136484
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhang S
中科院分区：
文献类型：
--
作者：
Han Y;Ye A;Zhang Y;Cai Z;Wang W;Sun L;Jiang S;Wu J;Yu K;Zhang S
已知RNA结合蛋白Musashi-2（Msi 2）在白血病发生中起关键作用，并导致急性髓性白血病（AML）的不良临床预后。然而，Msi 2沉默对AML治疗的影响仍然知之甚少。在这项研究中，我们使用慢病毒介导的RNA干扰靶向Msi 2研究细胞过程的变化和AML细胞系以及从AML患者中分离的原代AML细胞的潜在机制。我们发现Msi 2在AML细胞中高度表达，其缺失抑制Ki-67表达并导致体外和体内增殖降低。Msi 2基因沉默可使细胞周期阻滞于G 0/G1期，Cyclin D1表达减少，p21表达增加。Msi 2基因沉默通过下调Bcl-2表达和上调Bax表达诱导细胞凋亡。Akt、Erk 1/2和p38磷酸化的抑制也有助于Msi 2沉默介导的凋亡。最后，AML细胞中的Msi 2沉默也增强了它们对柔红霉素的化学敏感性。总之，我们的数据表明，Msi 2是一个有前途的基因治疗的目标，以优化传统的化疗药物在AML治疗。
RNA-binding protein Musashi-2 (Msi2) is known to play a critical role in leukemogenesis and contributes to poor clinical prognosis in acute myeloid leukemia (AML). However, the effect of Msi2 silencing on treatment for AML still remains poorly understood. In this study, we used lentivirus-mediated RNA interference targeting Msi2 to investigate the resulting changes in cellular processes and the underlying mechanisms in AML cell lines as well as primary AML cells isolated from AML patients. We found that Msi2 was highly expressed in AML cells, and its depletion inhibited Ki-67 expression and resulted in decreased in vitro and in vivo proliferation. Msi2 silencing induced cell cycle arrest in G0/G1 phase, with decreased Cyclin D1 and increased p21 expression. Msi2 silencing induced apoptosis through down-regulation of Bcl-2 expression and up-regulation of Bax expression. Suppression of Akt, Erk1/2 and p38 phosphorylation also contributed to apoptosis mediated by Msi2 silencing. Finally, Msi2 silencing in AML cells also enhanced their chemosensitivity to daunorubicin. Conclusively, our data suggest that Msi2 is a promising target for gene therapy to optimize conventional chemotherapeutics in AML treatment.