Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. Journal Article

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Authors: Velu, CS; Chaubey, A; Phelan, JD; Horman, SR; Wunderlich, M; Guzman, ML; Jegga, AG; Zeleznik-Le, NJ; Chen, J; Mulloy, JC; Cancelas, JA; Jordan, CT; Aronow, BJ; Marcucci, G; Bhat, B; Gebelein, B; Grimes, HL
Article Title: Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity.
Abstract: Acute myelogenous leukemia (AML) subtypes that result from oncogenic activation of homeobox (HOX) transcription factors are associated with poor prognosis. The HOXA9 transcription activator and growth factor independent 1 (GFI1) transcriptional repressor compete for occupancy at DNA-binding sites for the regulation of common target genes. We exploited this 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 inhibited in vitro leukemic colony forming activity and depleted in vivo leukemia-initiating cell activity of HOX-based leukemias, which led to leukemia-free survival in a murine AML model and delayed disease onset in xenograft models. 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.
Journal Title: The Journal of clinical investigation
ISSN: 1558-8238; 0021-9738
Publisher: Unknown  
Date Published: 2014