Abstract
Abstract The HoxA9 transcription activator and the Gfi1 transcriptional repressor compete for the regulation of common target genes. We exploited HoxA9 versus Gfi1 antagonism to identify the genes encoding microRNA-21 and microRNA-196b as transcriptional targets of Hox-based leukemia oncoproteins. Therapeutic inhibition of microRNA-21 and microRNA-196b significantly inhibits in vitro colony forming activity, and quantitatively depletes in vivo leukemia-initiating-cell activity of Hox-based leukemias leading to leukemia-free survival of murine AML and significant delay in disease onset in xenograft models. A novel microRNA target identification platform both validates therapeutic intervention and reveals biological impact of disrupting microRNA function. These data establish microRNA as functional effectors of endogenous HoxA9 and Hox-based leukemia oncoproteins, provide a concise in vivo platform to test RNA therapeutics, and suggest therapeutic value for microRNA antagonists in AML. Citation Format: Chinavenmeni S. Velu, Aditya Chaubey, James D. Phelan, Sara Meyer, Shane R. Horman, Mark Wunderlich, Monica L. Guzman, Anil G. Jegga, Nancy J. Zeleznik-Le, Jianjun Chen, James C. Mulloy, Jose A. Cancelas, Craig T. Jordan, Bruce J. Aronow, Guido Marcucci, Balkrishen Bhat, Brian Gebelein, H. Leighton Grimes. microRNA-mediated leukemia-initiating cell activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 979. doi:10.1158/1538-7445.AM2014-979
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