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Acute myeloid leukemia

Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia

Leukemia volume 29, pages 2143–2153 (2015)Cite this article

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Abstract

Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to ‘stemness’ and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (⩾60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, that is, miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.

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Acknowledgements

This study was supported by CA135332 (GM) CA102031 (GM) and CA140158 (GM and MAC) from National Cancer Institute, National Institutes of Health. AMD was supported by a Pelotonia postdoctoral research grant and AMD and RJL were supported by a Pelotonia Idea grant.

Author contributions

AMD, PN and GM designed the research; CDB, MAC and GM analyzed data and provided financial and administrative support for expression and methylation analyses of AML patients; AMD, PN, XH, DN, GF, HGO, PH, JK, KM, EH, MY, RJL, LJL, BNB, HW, CMC, RG, MAC, CDB and GM performed research and/or critically reviewed and analyzed the data; AMD, PN and GM wrote the paper; and all authors critically reviewed and edited the paper.

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Author notes

  1. A M Dorrance, P Neviani, C D Bloomfield and G Marcucci: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    A M Dorrance, P Neviani, G J Ferenchak, X Huang, P Hoellarbauer, J Khalife, E B Hill, M Yadav, C M Croce, R Garzon, M A Caligiuri & C D Bloomfield

  2. Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    A M Dorrance, P Neviani, G J Ferenchak, X Huang, D Nicolet, K S Maharry, P Hoellarbauer, J Khalife, E B Hill, M Yadav, R Garzon, M A Caligiuri & C D Bloomfield

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

    X Huang, R J Lee & L J Lee

  4. Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA

    X Huang, H G Ozer, R J Lee & L J Lee

  5. Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    D Nicolet & K S Maharry

  6. Department of Internal Medicine, Comparative Pathology and Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, OH, USA

    B N Bolon

  7. Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA

    C M Croce, R Garzon & G Marcucci

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  1. A M Dorrance
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  2. P Neviani
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Correspondence to A M Dorrance.

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Dorrance, A., Neviani, P., Ferenchak, G. et al. Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia. Leukemia 29, 2143–2153 (2015). https://doi.org/10.1038/leu.2015.139

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  • DOI: https://doi.org/10.1038/leu.2015.139

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