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