Abstract
Disruption of Runx1/AML1 subnuclear localization, either by a single amino acid substitution or by a chromosomal translocation [e.g., t(8;21)], is linked to the etiology of acute myeloid leukemia (AML). Here, we show that this defect induces a select set of micro-RNAs (miR) in myeloid progenitor cells and AML patients with t(8;21). Both Runx1 and the t(8;21)-encoded AML1-ETO occupy the miR-24-23-27 locus and reciprocally control miR-24 transcription. miR-24 directly downregulates mitogen-activated protein kinase (MAPK) phosphatase-7 and enhances phosphorylation of both c-jun-NH(2)-kinase and p38 kinases. Expression of miR-24 stimulates myeloid cell growth, renders proliferation independent of interleukin-3, and blocks granulocytic differentiation. Thus, compromised Runx1 function induces a miR-dependent mechanism that, through MAPK signaling, enhances myeloid proliferation but blocks differentiation--key steps that contribute to leukemia.
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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Blotting, Western
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Cell Differentiation
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Cell Nucleus / metabolism
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Cell Proliferation*
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Chromatin Immunoprecipitation
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 8 / genetics
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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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Dual-Specificity Phosphatases / genetics
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Dual-Specificity Phosphatases / metabolism*
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Granulocytes / metabolism
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Humans
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Immunoenzyme Techniques
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Interleukin-3 / metabolism
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Mitogen-Activated Protein Kinase Phosphatases / genetics
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Mitogen-Activated Protein Kinase Phosphatases / metabolism*
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Myeloid Progenitor Cells / physiology*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RUNX1 Translocation Partner 1 Protein
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Reverse Transcriptase Polymerase Chain Reaction
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Translocation, Genetic
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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Interleukin-3
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MIRN24 microRNA, human
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MicroRNAs
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Oncogene Proteins, Fusion
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RNA, Messenger
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RUNX1 Translocation Partner 1 Protein
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RUNX1 protein, human
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Phosphatases
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DUSP16 protein, human
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Dual-Specificity Phosphatases