Abstract
AML1-ETO is one of the most common chromosomal translocation products associated with acute myelogenous leukemia (AML). Patients carrying the AML1-ETO fusion gene exhibit an accumulation of granulocyte precursors in the bone marrow and the blood. Here, we describe a transgenic zebrafish line that enables inducible expression of the human AML1-ETO oncogene. Induced AML1-ETO expression in embryonic zebrafish causes a phenotype that recapitulates some aspects of human AML. Using this highly tractable model, we show that AML1-ETO redirects myeloerythroid progenitor cells that are developmentally programmed to adopt the erythroid cell fate into the granulocytic cell fate. This fate change is characterized by a loss of gata1 expression and an increase in pu.1 expression in myeloerythroid progenitor cells. Moreover, we identify scl as an early and essential mediator of the effect of AML1-ETO on hematopoietic cell fate. AML1-ETO quickly shuts off scl expression, and restoration of scl expression rescues the effects of AML1-ETO on myeloerythroid progenitor cell fate. These results demonstrate that scl is an important mediator of the ability of AML1-ETO to reprogram hematopoietic cell fate decisions, suggesting that scl may be an important contributor to AML1-ETO-associated leukemia. In addition, treatment of AML1-ETO transgenic zebrafish embryos with a histone deacetylase inhibitor, Trichostatin A, restores scl and gata1 expression, and ameliorates the accumulation of granulocytic cells caused by AML1-ETO. Thus, this zebrafish model facilitates in vivo dissection of AML1-ETO-mediated signaling, and will enable large-scale chemical screens to identify suppressors of the in vivo effects of AML1-ETO.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Blood Cells / cytology
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Blood Cells / drug effects
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Blood Cells / metabolism
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Cardiovascular System / cytology
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Cardiovascular System / drug effects
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Cardiovascular System / embryology
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Cardiovascular System / metabolism
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Cell Lineage* / drug effects
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Core Binding Factor Alpha 2 Subunit / metabolism*
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Down-Regulation / drug effects
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Down-Regulation / genetics*
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Embryo, Nonmammalian / cytology
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Embryo, Nonmammalian / drug effects
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Embryo, Nonmammalian / metabolism
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Erythroid Precursor Cells / cytology
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Erythroid Precursor Cells / drug effects
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Erythroid Precursor Cells / metabolism
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Erythropoiesis / drug effects
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GATA1 Transcription Factor / metabolism
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Gene Expression Regulation, Developmental / drug effects
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Hematopoietic System / cytology*
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Hematopoietic System / drug effects
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Humans
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Hydroxamic Acids / pharmacology
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Leukemia, Myeloid, Acute / blood
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / metabolism
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Oncogene Proteins, Fusion / metabolism*
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RUNX1 Translocation Partner 1 Protein
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Transcription, Genetic / drug effects
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Zebrafish / embryology
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Zebrafish / genetics*
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Zebrafish Proteins / genetics*
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Zebrafish Proteins / metabolism
Substances
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AML1-ETO fusion protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Core Binding Factor Alpha 2 Subunit
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GATA1 Transcription Factor
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Hydroxamic Acids
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins
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RUNX1 Translocation Partner 1 Protein
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Zebrafish Proteins
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gata1a protein, zebrafish
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tal1 protein, zebrafish
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trichostatin A