title: AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression.
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.
authors.affiliation: Developmental Biology Laboratory, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. jyeh1@partners.org
authors.forename: Jing-Ruey J
authors.initials: JR
authors.lastname: Yeh
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Munson
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Chao
authors.forename: Quinn P
authors.initials: QP
authors.lastname: Peterson
authors.forename: Calum A
authors.initials: CA
authors.lastname: Macrae
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002319:Cardiovascular System / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D050982:GATA1 Transcription Factor / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006413:Hematopoietic System / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000097:blood; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014158:Transcription, Genetic / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050982:GATA1 Transcription Factor; D006877:Hydroxamic Acids; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D029961:Zebrafish Proteins; C107844:AML1-ETO fusion protein, human; C494691:gata1a protein, zebrafish; C489367:tal1 protein, zebrafish; C012589:trichostatin A