Abstract
t(8;21) is one of the most frequent chromosomal translocations occurring in acute myeloid leukemia (AML) and is considered the leukemia-initiating event. The biologic and clinical significance of microRNA dysregulation associated with AML1/ETO expressed in t(8;21) AML is unknown. Here, we show that AML1/ETO triggers the heterochromatic silencing of microRNA-193a (miR-193a) by binding at AML1-binding sites and recruiting chromatin-remodeling enzymes. Suppression of miR-193a expands the oncogenic activity of the fusion protein AML-ETO, because miR-193a represses the expression of multiple target genes, such as AML1/ETO, DNMT3a, HDAC3, KIT, CCND1, and MDM2 directly, and increases PTEN indirectly. Enhanced miR-193a levels induce G(1) arrest, apoptosis, and restore leukemic cell differentiation. Our study identifies miR-193a and PTEN as targets for AML1/ETO and provides evidence that links the epigenetic silencing of tumor suppressor genes miR-193a and PTEN to differentiation block of myeloid precursors. Our results indicated a feedback circuitry involving miR-193a and AML1/ETO/DNMTs/HDACs, cooperating with the PTEN/PI3K signaling pathway and contributing to leukemogenesis in vitro and in vivo, which can be successfully targeted by pharmacologic disruption of the AML1/ETO/DNMTs/HDACs complex or enhancement of miR-193a in t(8;21)-leukemias.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methyltransferase 3A
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Down-Regulation / physiology
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Epigenesis, Genetic / physiology
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Gene Expression Regulation, Leukemic / physiology
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Gene Silencing / physiology
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HL-60 Cells
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism*
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Mice
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Mice, Nude
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MicroRNAs / genetics*
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Myelopoiesis / genetics
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Neoplasm Transplantation
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Binding / physiology
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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RUNX1 Translocation Partner 1 Protein
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Signal Transduction / genetics*
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U937 Cells
Substances
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AML1-ETO fusion protein, human
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CCND1 protein, human
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Core Binding Factor Alpha 2 Subunit
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DNMT3A protein, human
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Dnmt3a protein, mouse
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MIRN193 microRNA, human
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MicroRNAs
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Oncogene Proteins, Fusion
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RUNX1 Translocation Partner 1 Protein
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Cyclin D1
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Proto-Oncogene Proteins c-kit
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PTEN Phosphohydrolase
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PTEN protein, human
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Histone Deacetylases
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histone deacetylase 3