Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity.
basic_science · Level V
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- Record sourced from PubMed, PMID 24334453.
- Also identified by DOI 10.1172/JCI66005 and PMC identifier 3871218.
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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.
Medical subject headings
- Antineoplastic Combined Chemotherapy Protocols
- Leukemia, Myeloid, Acute
- MicroRNAs
- Neoplastic Stem Cells