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

• Published in: Blood Vol. 106; no. 2; pp. 477 - 484
• Main Authors: Rodrigues, Neil P., Janzen, Viktor, Forkert, Randolf, Dombkowski, David M., Boyd, Ashleigh S., Orkin, Stuart H., Enver, Tariq, Vyas, Paresh, Scadden, David T.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.07.2005; The Americain Society of Hematology
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cell Cycle; Cells, Cultured; Combined treatment; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Female; GATA2 Transcription Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Heterozygote; Homeostasis; Male; Medical sciences; Mice; Mice, Knockout; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factors - deficiency; Transcription Factors - genetics; Treatment. General aspects; Tumors; Human; Animal model; Stem cell; Rodentia; Hematopoietic cell; Homeostasis; Transcription factor GATA2; Vertebrata; Mammalia; Mouse; Hematopoiesis; Cell cycle; Bone marrow; Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-08-2989

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.