D'Abundo L, Callegari E, Bresin A, Chillemi A, Elamin B K, Guerriero P, Huang X, Saccenti E, Hussein E M A A, Casciano F, Secchiero P, Zauli G, Calin G A, Russo G, Lee L J, Croce C M, Marcucci G, Sabbioni S, Malavasi F, Negrini M
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Laboratorio di Oncologia Molecolare, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.
Oncogene. 2017 Nov 23;36(47):6617-6626. doi: 10.1038/onc.2017.269. Epub 2017 Aug 7.
Dysregulation of microRNAs (miRNAs) plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). The Eμ-TCL1 transgenic mouse develops a form of leukemia that is similar to the aggressive type of human B-CLL, and this valuable model has been widely used for testing novel therapeutic approaches. Here, we adopted this model to investigate the potential effects of miR-26a, miR-130an and antimiR-155 in CLL therapy. Improved delivery of miRNA molecules into CLL cells was obtained by developing a novel system based on lipid nanoparticles conjugated with an anti-CD38 monoclonal antibody. This methodology has proven to be highly effective in delivering miRNA molecules into leukemic cells. Short- and long-term experiments showed that miR-26a, miR-130a and anti-miR-155 increased apoptosis after in vitro and in vivo treatment. Of this miRNA panel, miR-26a was the most effective in reducing leukemic cell expansion. Following long-term treatment, apoptosis was readily detectable by analyzing cleavage of PARP and caspase-7. These effects could be directly attributed to miR-26a, as confirmed by significant downregulation of its proven targets, namely cyclin-dependent kinase 6 and Mcl1. The results of this study are relevant to two distinct areas. The first is related to the design of a technical strategy and to the selection of CD38 as a molecular target on CLL cells, both consenting efficient and specific intracellular transfer of miRNA. The original scientific finding inferred from the above approach is that miR-26a can elicit in vivo anti-leukemic activities mediated by increased apoptosis.
微小RNA（miRNA）失调在慢性淋巴细胞白血病（CLL）的发病机制中起重要作用。Eμ-TCL1转基因小鼠会发生一种类似于人类侵袭性B-CLL的白血病，这个有价值的模型已被广泛用于测试新的治疗方法。在此，我们采用该模型研究miR-26a、miR-130a和抗miR-155在CLL治疗中的潜在作用。通过开发一种基于与抗CD38单克隆抗体偶联的脂质纳米颗粒的新系统，实现了miRNA分子向CLL细胞的更有效递送。该方法已被证明在将miRNA分子递送至白血病细胞中非常有效。短期和长期实验表明，miR-26a、miR-130a和抗miR-155在体外和体内治疗后均增加了细胞凋亡。在这个miRNA组合中，miR-26a在减少白血病细胞增殖方面最有效。长期治疗后，通过分析PARP和caspase-7的裂解很容易检测到细胞凋亡。这些作用可直接归因于miR-26a，其已证实的靶标细胞周期蛋白依赖性激酶6和Mcl1的显著下调证实了这一点。本研究结果与两个不同领域相关。第一个与技术策略的设计以及将CD38选为CLL细胞上的分子靶标有关，这两者都有助于miRNA进行高效且特异性的细胞内转移。从上述方法推断出的原始科学发现是，miR-26a可通过增加细胞凋亡引发体内抗白血病活性。
