Ma Wenjuan, Liu Jian, Xie Jundan, Zhang Xiuyan, Zhou Haixia, Yao Hong, Zhang Weiqi, Guo Dawei, Zhu Lingying, Xiao Lun, Wu Depei, Xu Haiyan, Chen Suning, Zhao Yun
J Biomed Nanotechnol. 2015 Nov;11(11):1961-74. doi: 10.1166/jbn.2015.2147.
Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring Philadelphia chromosome (Ph) to generate BCR-ABL fusion gene whose protein product has deregulated tyrosine kinase activity. Specific inhibitors against BCR-ABL, such as Imatinib mesylate (IM), have greatly improved CML management; however, no single agent is a cure yet. Delivery of microRNA (miRNA) using non-viral vectors has been utilized to inhibit various cancer cells; however, the efficacy of this approach to target CML stem/progenitor cells has not been elucidated. In this study, we firstly validated that spermine-introduced pullulan (Ps) was a robust non-viral vector for delivery of miRNA to CML cells, including the CD34+ cells from clinical isolates. We then found that the miR-181a/RALA (V-ral simian leukemia viral oncogene homolog A) axis was aberrantly expressed in the CML CD34+ cells. The delivery of miR-181a specifically inhibited the growth of CML CD34+ cells, possibly via the inhibition of RALA. In contrast, miR-181a did not evidently affect the normal hematopoietic CD34+ cells. In addition, miR-181a increased IM sensitivity of the CD34+ CML cells. Taken together, we have therefore demonstrated that the delivery of miR-181a using Ps to CML stem/progenitor cells leads to their growth inhibition and enhancement of IM sensitivity, which will possibly be beneficial to CML treatment.
慢性髓性白血病（CML）起源于正常造血干细胞获得费城染色体（Ph），从而产生BCR-ABL融合基因，其蛋白质产物具有失调的酪氨酸激酶活性。针对BCR-ABL的特异性抑制剂，如甲磺酸伊马替尼（IM），已大大改善了CML的治疗；然而，尚无单一药物可治愈该病。使用非病毒载体递送微小RNA（miRNA）已被用于抑制各种癌细胞；然而，这种靶向CML干/祖细胞方法的疗效尚未阐明。在本研究中，我们首先验证了引入精胺的支链淀粉（Ps）是一种强大的非病毒载体，可将miRNA递送至CML细胞，包括临床分离株中的CD34+细胞。然后我们发现miR-181a/RALA（V-ral猴白血病病毒癌基因同源物A）轴在CML CD34+细胞中异常表达。miR-181a的递送特异性抑制了CML CD34+细胞的生长，可能是通过抑制RALA实现的。相比之下，miR-181a对正常造血CD34+细胞没有明显影响。此外，miR-181a增加了CD34+ CML细胞对IM的敏感性。综上所述，我们证明了使用Ps将miR-181a递送至CML干/祖细胞可导致其生长受到抑制并增强对IM的敏感性，这可能对CML治疗有益。
