PUBLICATION
AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression
- Authors
- Yeh, J.R., Munson, K.M., Chao, Y.L., Peterson, Q.P., MacRae, C.A., and Peterson, R.T.
- ID
- ZDB-PUB-071227-16
- Date
- 2008
- Source
- Development (Cambridge, England) 135(2): 401-410 (Journal)
- Registered Authors
- MacRae, Calum A., Peterson, Randall, Yeh, Jing-Ruey (Joanna)
- Keywords
- Hematopoiesis, Myeloid, Leukemia, Zebrafish
- MeSH Terms
-
- Hematopoietic System/cytology*
- Hematopoietic System/drug effects
- Blood Cells/cytology
- Blood Cells/drug effects
- Blood Cells/metabolism
- GATA1 Transcription Factor/metabolism
- Humans
- Zebrafish/embryology
- Zebrafish/genetics*
- Leukemia, Myeloid, Acute/blood
- Core Binding Factor Alpha 2 Subunit/metabolism*
- Transcription, Genetic/drug effects
- Animals, Genetically Modified
- Monocytes/cytology
- Monocytes/drug effects
- Monocytes/metabolism
- Cell Lineage*/drug effects
- Gene Expression Regulation, Developmental/drug effects
- Erythropoiesis/drug effects
- Animals
- Oncogene Proteins, Fusion/metabolism*
- Cardiovascular System/cytology
- Cardiovascular System/drug effects
- Cardiovascular System/embryology
- Cardiovascular System/metabolism
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Proto-Oncogene Proteins/genetics*
- Proto-Oncogene Proteins/metabolism
- Hydroxamic Acids/pharmacology
- Erythroid Precursor Cells/cytology
- Erythroid Precursor Cells/drug effects
- Erythroid Precursor Cells/metabolism
- Basic Helix-Loop-Helix Transcription Factors/genetics*
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Down-Regulation/drug effects
- Down-Regulation/genetics*
- PubMed
- 18156164 Full text @ Development
Citation
Yeh, J.R., Munson, K.M., Chao, Y.L., Peterson, Q.P., MacRae, C.A., and Peterson, R.T. (2008) AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression. Development (Cambridge, England). 135(2):401-410.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping