[HTML][HTML] Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity

CS Velu, A Chaubey, JD Phelan… - The Journal of …, 2014 - Am Soc Clin Investig
CS Velu, A Chaubey, JD Phelan, SR Horman, M Wunderlich, ML Guzman, AG Jegga
The Journal of clinical investigation, 2014Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation