AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression

Jing Ruey J. Yeh, Kathleen M. Munson, Yvonne L. Chao, Quinn P. Peterson, Calum A. MacRae, Randall T. Peterson

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

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 gatal 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 hernatopoietic 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 gatal 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.

Original languageEnglish (US)
Pages (from-to)401-410
Number of pages10
JournalDevelopment
Volume135
Issue number2
DOIs
StatePublished - Jan 2008

Keywords

  • Hematopoiesis
  • Leukemia
  • Myeloid
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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