Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis
2005; Elsevier BV; Volume: 106; Issue: 2 Linguagem: Inglês
10.1182/blood-2004-08-2989
ISSN1528-0020
AutoresNeil P. Rodrigues, Viktor Janzen, Randolf Forkert, David Dombkowski, Ashleigh S. Boyd, Stuart H. Orkin, Tariq Enver, Paresh Vyas, David T. Scadden,
Tópico(s)Epigenetics and DNA Methylation
ResumoThe 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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