AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression

Yeh, J.R., Munson, K.M., Chao, Y.L., Peterson, Q.P., MacRae, C.A., and Peterson, R.T.
Development (Cambridge, England)   135(2): 401-410 (Journal)
Registered Authors
MacRae, Calum A., Peterson, Randall, Yeh, Jing-Ruey (Joanna)
Hematopoiesis, Myeloid, Leukemia, Zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Basic Helix-Loop-Helix Transcription Factors/genetics*
  • Basic Helix-Loop-Helix Transcription Factors/metabolism
  • Blood Cells/cytology
  • Blood Cells/drug effects
  • Blood Cells/metabolism
  • Cardiovascular System/cytology
  • Cardiovascular System/drug effects
  • Cardiovascular System/embryology
  • Cardiovascular System/metabolism
  • Cell Lineage*/drug effects
  • Core Binding Factor Alpha 2 Subunit/metabolism*
  • Down-Regulation/drug effects
  • Down-Regulation/genetics*
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Erythroid Precursor Cells/cytology
  • Erythroid Precursor Cells/drug effects
  • Erythroid Precursor Cells/metabolism
  • Erythropoiesis/drug effects
  • GATA1 Transcription Factor/metabolism
  • Gene Expression Regulation, Developmental/drug effects
  • Hematopoietic System/cytology*
  • Hematopoietic System/drug effects
  • Humans
  • Hydroxamic Acids/pharmacology
  • Leukemia, Myeloid, Acute/blood
  • Monocytes/cytology
  • Monocytes/drug effects
  • Monocytes/metabolism
  • Oncogene Proteins, Fusion/metabolism*
  • Proto-Oncogene Proteins/genetics*
  • Proto-Oncogene Proteins/metabolism
  • Transcription, Genetic/drug effects
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
18156164 Full text @ Development
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes