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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Presented in part at the 103rd Annual Meeting of the American Association for Cancer Research, Chicago, IL, April 2012, and published in abstract form.
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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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DOI: https://doi.org/10.1038/leu.2012.342
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