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.
authors: Chinavenmeni S
authors: CS
authors: Velu
authors: Aditya
authors: A
authors: Chaubey
authors: James D
authors: JD
authors: Phelan
authors: Shane R
authors: SR
authors: Horman
authors: Mark
authors: M
authors: Wunderlich
authors: Monica L
authors: ML
authors: Guzman
authors: Anil G
authors: AG
authors: Jegga
authors: Nancy J
authors: NJ
authors: Zeleznik-Le
authors: Jianjun
authors: J
authors: Chen
authors: James C
authors: JC
authors: Mulloy
authors: Jose A
authors: JA
authors: Cancelas
authors: Craig T
authors: CT
authors: Jordan
authors: Bruce J
authors: BJ
authors: Aronow
authors: Guido
authors: G
authors: Marcucci
authors: Balkrishen
authors: B
authors: Bhat
authors: Brian
authors: B
authors: Gebelein
authors: H Leighton
authors: HL
authors: Grimes
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000502:physiology*; D054735:Phosphorothioate Oligonucleotides / Q000235:genetics; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D018398:Homeodomain Proteins; C542543:MIRN196 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D054735:Phosphorothioate Oligonucleotides; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C083400:PBX1 protein, human; D003561:Cytarabine; D004317:Doxorubicin