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First published online December 21, 2007
doi: 10.1242/10.1242/dev.008904

Development 135, 401-410 (2008)
Published by The Company of Biologists 2008
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AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression

Jing-Ruey J. Yeh1,2,3,*, Kathleen M. Munson1,2,3, Yvonne L. Chao1,2, Quinn P. Peterson1,2, Calum A. MacRae1,2 and Randall T. Peterson1,2,3,*

1 Developmental Biology Laboratory, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
2 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

* Authors for correspondence (e-mails: jyeh1{at}partners.org; peterson{at}cvrc.mgh.harvard.edu)

Accepted 18 October 2007

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.

Key words: Hematopoiesis, Myeloid, Leukemia, Zebrafish




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F. Dayyani, J. Wang, J.-R. J. Yeh, E.-Y. Ahn, E. Tobey, D.-E. Zhang, I. D. Bernstein, R. T. Peterson, and D. A. Sweetser
Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival
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[Abstract] [Full Text] [PDF]


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