AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression

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

Research output: Contribution to journalArticle

88 Citations (Scopus)

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 1 2008
Externally publishedYes

Fingerprint

Zebrafish
Down-Regulation
Stem Cells
Acute Myeloid Leukemia
trichostatin A
Genetic Translocation
Erythroid Cells
Histone Deacetylase Inhibitors
Gene Fusion
Oncogenes
Granulocytes
Dissection
Leukemia
Embryonic Structures
Bone Marrow
Phenotype
Therapeutics

Keywords

  • Hematopoiesis
  • Leukemia
  • Myeloid
  • Zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Yeh, J. R. J., Munson, K. M., Chao, Y. L., Peterson, Q., MacRae, C. A., & Peterson, R. T. (2008). AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression. Development, 135(2), 401-410. https://doi.org/10.1242/dev.008904

AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression. / Yeh, Jing Ruey J.; Munson, Kathleen M.; Chao, Yvonne L.; Peterson, Quinn; MacRae, Calum A.; Peterson, Randall T.

In: Development, Vol. 135, No. 2, 01.01.2008, p. 401-410.

Research output: Contribution to journalArticle

Yeh, JRJ, Munson, KM, Chao, YL, Peterson, Q, MacRae, CA & Peterson, RT 2008, 'AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression', Development, vol. 135, no. 2, pp. 401-410. https://doi.org/10.1242/dev.008904
Yeh, Jing Ruey J. ; Munson, Kathleen M. ; Chao, Yvonne L. ; Peterson, Quinn ; MacRae, Calum A. ; Peterson, Randall T. / AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression. In: Development. 2008 ; Vol. 135, No. 2. pp. 401-410.
@article{7d4eb681f4a64ab6a6d43f52e1182ae8,
title = "AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression",
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.",
keywords = "Hematopoiesis, Leukemia, Myeloid, Zebrafish",
author = "Yeh, {Jing Ruey J.} and Munson, {Kathleen M.} and Chao, {Yvonne L.} and Quinn Peterson and MacRae, {Calum A.} and Peterson, {Randall T.}",
year = "2008",
month = "1",
day = "1",
doi = "10.1242/dev.008904",
language = "English (US)",
volume = "135",
pages = "401--410",
journal = "Development (Cambridge)",
issn = "0950-1991",
publisher = "Company of Biologists Ltd",
number = "2",

}

TY - JOUR

T1 - AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression

AU - Yeh, Jing Ruey J.

AU - Munson, Kathleen M.

AU - Chao, Yvonne L.

AU - Peterson, Quinn

AU - MacRae, Calum A.

AU - Peterson, Randall T.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

KW - Hematopoiesis

KW - Leukemia

KW - Myeloid

KW - Zebrafish

UR - http://www.scopus.com/inward/record.url?scp=38949180229&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38949180229&partnerID=8YFLogxK

U2 - 10.1242/dev.008904

DO - 10.1242/dev.008904

M3 - Article

C2 - 18156164

AN - SCOPUS:38949180229

VL - 135

SP - 401

EP - 410

JO - Development (Cambridge)

JF - Development (Cambridge)

SN - 0950-1991

IS - 2

ER -