Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis

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