Abstract
Hematopoietic transcription factors are involved in chromosomal translocations, which generate fusion proteins contributing to leukemia pathogenesis. Analysis of patient's primary leukemia blasts revealed that those carrying the t(8;21) generating AML1/ETO, the most common acute myeloid leukemia-associated fusion protein, display low levels of a microRNA-223 (miR-223), a regulator of myelopoiesis. Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation. Here, we identify an additional action for a leukemia fusion protein linking the epigenetic silencing of a microRNA locus to the differentiation block of leukemia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / physiology*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / physiology*
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Epigenesis, Genetic*
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Gene Expression Regulation, Leukemic*
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Gene Silencing*
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HL-60 Cells
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Humans
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Karyotyping
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Leukemia / genetics*
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MicroRNAs / genetics*
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MicroRNAs / physiology
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Models, Biological
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Myelopoiesis
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Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / physiology*
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RNA, Messenger / physiology*
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RUNX1 Translocation Partner 1 Protein
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Transcription Factors / genetics*
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Transcription Factors / physiology*
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Transcriptional Activation
Substances
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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MIRN223 microRNA, human
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MicroRNAs
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Oncogene Proteins
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Proto-Oncogene Proteins
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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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RUNX1T1 protein, human
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Transcription Factors