AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression
Author:
Yeh Jing-Ruey J.123, Munson Kathleen M.123, Chao Yvonne L.12, Peterson Quinn P.12, MacRae Calum A.12, Peterson Randall T.123
Affiliation:
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.
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.1expression 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.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference57 articles.
1. Alcalay, M., Meani, N., Gelmetti, V., Fantozzi, A., Fagioli, M.,Orleth, A., Riganelli, D., Sebastiani, C., Cappelli, E., Casciari, C. et al. (2003). Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J. Clin. Invest.112,1751-1761. 2. Begley, C. G. and Green, A. R. (1999). The SCL gene: from case report to critical hematopoietic regulator. Blood93,2760-2770. 3. Bennett, C. M., Kanki, J. P., Rhodes, J., Liu, T. X., Paw, B. H., Kieran, M. W., Langenau, D. M., Delahaye-Brown, A., Zon, L. I., Fleming,M. D. et al. (2001). Myelopoiesis in the zebrafish, Danio rerio. Blood98,643-651. 4. Bonnet, D. and Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med.3, 730-737. 5. Borregaard, N., Theilgaard-Monch, K., Sorensen, O. E. and Cowland, J. B. (2001). Regulation of human neutrophil granule protein expression. Curr. Opin. Hematol.8, 23-27.
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