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

Oncogene volume 36, pages 6617–6626 (2017)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by funds from the Italian Association for Cancer Research (AIRC Special program 5xmille n.9980) and the University of Ferrara to MN, from the US National Cancer Institute grant CA19-7706 to CMC, from FIRB Programme of the Ministry of University and Research (Rome, Italy), Fondazione Cassa di Risparmio di Torino and Fondazione Ricerca Molinette Torino to FM.

Author information

Author notes

  1. L D’Abundo and E Callegari: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

    L D’Abundo, E Callegari, A Bresin, P Guerriero, E M A A Hussein & M Negrini

  2. Laboratorio di Oncologia Molecolare, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy

    A Bresin & G Russo

  3. Department of Medical Sciences, Laboratory of Immunogenetics, University of Torino, Torino, Italy

    A Chillemi & F Malavasi

  4. Laboratorio di Immunologia dei Trapianti, Città della Salute e della Scienza, Torino, Italy

    A Chillemi & F Malavasi

  5. Microbiology Department, Faculty of Medical laboratory Sciences, University of Khartoum, Khartoum, Sudan

    B K Elamin

  6. Microbiology Department, College of Medicine, University of Bisha, Bisha, Saudi Arabia

    B K Elamin

  7. Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA

    X Huang & L J Lee

  8. Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA

    X Huang & L J Lee

  9. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    X Huang & C M Croce

  10. Department of Medical Sciences, Hematology Section, University of Ferrara, University Hospital Arcispedale S. Anna, Ferrara, Italy

    E Saccenti

  11. Hematology and Immunohematology Department, Faculty of Medical laboratory Sciences, University of Khartoum, Khartoum, Sudan

    E M A A Hussein

  12. Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy

    F Casciano, P Secchiero & G Zauli

  13. Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G A Calin

  14. Gehr Family Center For Leukemia Research Hematologic Malignancies Institute City of Hope, Duarte, CA, USA

    G Marcucci

  15. Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

    S Sabbioni

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  1. L D’Abundo
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  2. E Callegari
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  8. E Saccenti
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Correspondence to M Negrini.

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Supplementary Information accompanies this paper on the Oncogene website

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D’Abundo, L., Callegari, E., Bresin, A. et al. Anti-leukemic activity of microRNA-26a in a chronic lymphocytic leukemia mouse model. Oncogene 36, 6617–6626 (2017). https://doi.org/10.1038/onc.2017.269

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  • DOI: https://doi.org/10.1038/onc.2017.269

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