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Blood, 1 January 2006, Vol. 107, No. 1, pp. 87-97.
Prepublished online as a Blood First Edition Paper on September 6, 2005; DOI 10.1182/blood-2005-07-2740.
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Submitted July 11, 2005
Accepted August 24, 2005
An early block to erythro-megakaryocytic development conferred by loss of transcription factor GATA-1
David L Stachura, Stella T Chou, and Mitchell J Weiss*
Cell and Molecular Biology Graduate Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
The Children's Hospital of Philadelphia, Division of Hematology and the University of Pennsylvania, Philadelphia, PA, USA
* Corresponding author; email: weissmi{at}email.chop.edu.
Transcription factor GATA-1 is essential at multiple stages of hematopoiesis. Murine gene targeting and analysis of naturally occurring human mutations demonstrate that GATA-1 drives the maturation of committed erythroid precursors and megakaryocytes. Prior studies also suggest additional, poorly defined, roles for GATA-1 at earlier stages of erythro-megakaryocytic differentiation. To investigate these functions further, we stimulated Gata1- murine embryonic stem cell-derived hematopoietic cultures with thrombopoietin, a multilineage cytokine. Initially, the cultures generated a wave of mutant megakaryocytes. However, these were rapidly overgrown by a unique population of thrombopoietin-dependent blasts that express immature markers and proliferate indefinitely. Importantly, upon restoration of GATA-1 function, these cells differentiated into both erythroid and megakaryocytic lineages, suggesting that they represent bipotential progenitors. Identical cells are also present in vivo, as indicated by flow cytometry and culture analysis of fetal livers from Gata1- chimeric mice. Our findings indicate that loss of GATA-1 impairs the maturation of megakaryocyte-erythroid progenitors. This defines a new role for GATA-1 at a relatively early stage of hematopoiesis and provides potential insight into recent discoveries that human GATA1 mutations promote acute megakaryoblastic leukemia, a clonal malignancy with features of both erythroid and megakaryocyte maturation.
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