Anti-leukemic activity of microRNA-26a in a chronic lymphocytic leukemia mouse model

• Published in: Oncogene Vol. 36; no. 47; pp. 6617 - 6626
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.11.2017; Nature Publishing Group
• Subjects: 631/67/1059/602; 631/67/1990/283/1895; ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - genetics; Animals; Antibodies, Monoclonal, Murine-Derived - chemistry; Apoptosis; Apoptosis - drug effects; Care and treatment; Caspase; Caspase 7 - metabolism; Caspase-7; CD38 antigen; Cell Biology; Cell Line, Tumor; Chronic lymphocytic leukemia; Cyclin-dependent kinase; Cyclin-dependent kinase 6; Cyclin-Dependent Kinase 6 - genetics; Cyclin-dependent kinases; Development and progression; Down-Regulation; Drug Delivery Systems; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Lipids - chemistry; Lymphatic leukemia; Mcl-1 protein; Medicine; Medicine & Public Health; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Mice; Mice, Transgenic; MicroRNA; MicroRNAs; MicroRNAs - administration & dosage; MicroRNAs - antagonists & inhibitors; MicroRNAs - therapeutic use; miRNA; Monoclonal antibodies; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Nanoparticles; Nanoparticles - chemistry; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - genetics; Oncology; original-article; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins - genetics; Rodents; Transgenic mice; Italy
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.269

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.