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Blood, 15 July 2005, Vol. 106, No. 2, pp. 477-484.
Prepublished online as a Blood First Edition Paper on April 5, 2005; DOI 10.1182/blood-2004-08-2989.
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HEMATOPOIESIS
Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis
Neil P. Rodrigues,
Viktor Janzen,
Randolf Forkert,
David M. Dombkowski,
Ashleigh S. Boyd,
Stuart H. Orkin,
Tariq Enver,
Paresh Vyas, and
David T. Scadden
From the Center for Regenerative Medicine and Technology, Massachusetts General Hospital, the Department of Pediatric Oncology, Children's Hospital and the Dana Farber Cancer Institute, Harvard Medical School, and the Howard Hughes Medical Institute, Boston, MA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA; the Department of Haematology and the MRC Haematology Unit, Weatherall Institute of Molecular Medicine, the Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, United Kingdom.
The zinc finger transcription factor GATA-2 plays a fundamental role in generating hematopoietic stem-cells in mammalian development. Less well defined is whether GATA-2 participates in adult stem-cell regulation, an issue we addressed using GATA-2 heterozygote mice that express reduced levels of GATA-2 in hematopoietic cells. While GATA-2+/– mice demonstrated decreases in some colony-forming progenitors, the most prominent changes were observed within the stem-cell compartment. Heterozygote bone marrow had a lower abundance of Lin–c-kit+Sca-1+CD34– cells and performed poorly in competitive transplantation and quantitative week-5 cobblestone area–forming cell (CAFC) assays. Furthermore, a stem-cell–enriched population from GATA1+/– marrow was more quiescent and exhibited a greater frequency of apoptotic cells associated with decreased expression of the antiapoptotic gene Bcl-xL. Yet the self-renewal potential of the +/– stem-cell compartment, as judged by serial transplantations, was unchanged. These data indicate compromised primitive cell proliferation and survival in the setting of a lower GATA-2 gene dose without a change in the differentiation or self-renewal capacity of the stem-cells that remain. Thus, GATA-2 dose regulates adult stem-cell homeostasis by affecting select aspects of stem cell function.
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