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Acute Leukemias

Increased anti-leukemic activity of decitabine via AR-42-induced upregulation of miR-29b: a novel epigenetic-targeting approach in acute myeloid leukemia

Leukemia volume 27, pages 871–878 (2013)Cite this article

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Abstract

Histone deacetylase (HDAC) inhibitors either alone or in combination with hypomethylating agents have limited clinical effect in acute myeloid leukemia (AML). Previously, we demonstrated that AML patients with higher miR (microRNA)-29b expression had better response to the hypomethylating agent decitabine. Therefore, an increase in miR-29b expression preceding decitabine treatment may provide a therapeutic advantage. We previously showed that miR-29b expression is suppressed by a repressor complex that includes HDACs. Thus, HDAC inhibition may increase miR-29b expression. We hypothesized that priming AML cells with the novel HDAC inhibitor (HDACI) AR-42 would result in increased response to decitabine treatment via upregulation of miR-29b. Here, we show that AR-42 is a potent HDACI in AML, increasing miR-29b levels and leading to downregulation of known miR-29b targets (that is, SP1, DNMT1, DNMT3A and DNMT3B). We then demonstrated that the sequential administration of AR-42 followed by decitabine resulted in a stronger anti-leukemic activity in vitro and in vivo than decitabine followed by AR-42 or either drug alone. These preclinical results with AR-42 priming before decitabine administration represent a promising, novel treatment approach and a paradigm shift with regard to the combination of epigenetic-targeting compounds in AML, where decitabine has been traditionally given before HDACIs.

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Acknowledgements

Supported in part by CA158350, CA102031, CA140158, The Coleman Leukemia Research Foundation (SS), The Harry Mangurian foundation, NIH T32 grant 60032104 (AM), K12CA133250 (AW). AW is a Paul Calabresi Clinical Scholar and a scholar of the American Society of Hematology-Amos Medical Faculty Development Program. We thank Donna Bucci and the Leukemia Tissue Bank for assistance with the primary AML samples. We would like to thank Samuel Kulp, DVM, PhD for assistance with AR-42.

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Author notes

  1. A Mims and A R Walker: These authors contributed equally to this work.

  2. S Schwind and G Marcucci: These senior authors contributed equally to this work.

Authors and Affiliations

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

    A Mims, A R Walker, J Sun, H Wang, R Santhanam, A M Dorrance, C Walker, P Hoellerbauer, K K Chan, R B Klisovic, M A Caligiuri, J C Byrd, K Mrózek, C D Bloomfield, W Blum, R Garzon, S Schwind & G Marcucci

  2. NSF Nanoscale Science and Engineering Center, The Ohio State University, Columbus, OH, USA

    X Huang & L James Lee

  3. Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    H Wang, K K Chan, C-S Chen & S Jacob

  4. Department of Molecular, Cellular, and Developmental Biology, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    S S Tarighat & D Perrotti

  5. Department of Microbiology, Division of Human Cancer Genetics and The Ohio State University Comprehensive Cancer Center, Virology, Immunology, and Medical Genetics, Columbus, OH, USA

    D Perrotti & G Marcucci

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Correspondence to G Marcucci.

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Additional information

Presented in part at the 103rd Annual Meeting of the American Association for Cancer Research, Chicago, IL, April 2012, and published in abstract form.

Author contributions

AM, JS, RS, AD, CW, PH, XH, ST and SS performed experiments. AM, HW, XH, KKC, DP, CSC, RG, SS and GM designed experiments and analyzed data. AM, AW, LJL, SJ, KM, CDB, SS and GM wrote the manuscript. All the authors approved the manuscript. AW, RBK, RG, WB, MC, JCB and GM were involved directly or indirectly in care of patients or sample procurement.

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Mims, A., Walker, A., Huang, X. et al. Increased anti-leukemic activity of decitabine via AR-42-induced upregulation of miR-29b: a novel epigenetic-targeting approach in acute myeloid leukemia. Leukemia 27, 871–878 (2013). https://doi.org/10.1038/leu.2012.342

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