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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Base Sequence
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Binding Sites
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Combined Modality Therapy
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Cytarabine / administration & dosage
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DNA-Binding Proteins / metabolism
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Doxorubicin / administration & dosage
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Gene Expression Regulation, Leukemic
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Homeodomain Proteins / metabolism
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Humans
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Induction Chemotherapy
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / pathology
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Leukemia, Myeloid, Acute / therapy
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, SCID
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Neoplasm Proteins / metabolism
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Neoplastic Stem Cells / physiology*
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Phosphorothioate Oligonucleotides / genetics
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Pre-B-Cell Leukemia Transcription Factor 1
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Protein Binding
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Proto-Oncogene Proteins / metabolism
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Regulatory Sequences, Nucleic Acid
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Transcription Factors / metabolism
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Transcriptome
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Xenograft Model Antitumor Assays
Substances
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DNA-Binding Proteins
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GFI1 protein, human
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Homeodomain Proteins
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MIRN196 microRNA, human
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MIRN21 microRNA, human
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MicroRNAs
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Neoplasm Proteins
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Phosphorothioate Oligonucleotides
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Pre-B-Cell Leukemia Transcription Factor 1
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Proto-Oncogene Proteins
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Transcription Factors
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homeobox protein HOXA9
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PBX1 protein, human
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Cytarabine
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Doxorubicin