HEMATOPOIESIS AND STEM CELLS The differential activities of Runx1 promoters define milestones during embryonic hematopoiesis

The transcription factor RUNX1/AML1 is a master regulator of hematopoietic de-velopment. Its spatiotemporal expres-sion is tightly regulated during embry-onic development and is under the control of 2 alternative promoters, distal and proximal. Despite the functional significance of Runx1, the relative and specific activities of these 2 promoters remain largely uncharacterized. To in-vestigate these activities, we intro-duced 2 reporter genes under the con-trol of the proximal and distal promoters in embryonic stem cell and transgenic mouse lines. Our study reveals that both in vitro and in vivo the proximal Runx1 isoform marks a hemogenic endothelium cell population, whereas the subsequent expression of distal Runx1 defines fully committed defini-tive hematopoietic progenitors. Interest-ingly, hematopoietic commitment in dis-tal Runx1 knockout embryos appears normal. Altogether, our data demon-strate that the differential activities of the 2 Runx1 promoters define mile-stones of hematopoietic development and suggest that the proximal isoform plays a critical role in the generation of hematopoietic cells from hemogenic en-dothelium. Identification and access to the discrete stages of hematopoietic development defined by the activities of the Runx1 promoters will provide the opportunity to further explore the cellu-lar and molecular mechanisms of hema-topoietic development. (Blood. 2009; 114:5279-5289