| First Author | Velu CS | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 1 | Pages | 222-36 |
| PubMed ID | 24334453 | Mgi Jnum | J:207619 |
| Mgi Id | MGI:5559253 | Doi | 10.1172/JCI66005 |
| Citation | Velu CS, et al. (2014) Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. J Clin Invest 124(1):222-36 |
| abstractText | 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. |
