Using diverse loss- and gain-of-function murine models, we have established that Mll1 is essential for the development of HSCs in the aorta-gonad-mesonephros (AGM) region (PMID15030765). Using pluripotent cells, we have shown that MLL1 levels are critical for the emergence of multipotent hematopoietic progenitors from hemogenic endothelium (PMID15556871 & 31951812). Unique vascular defects observed in germline Mll1 knockout embryos also may contribute to early hematopoietic phenotypes (Figure). Hematopoietic-targeted Mll1 deletion illustrated that fetal liver HSCs develop and expand throughout gestation but fail to acquire functional properties of adult HSCs (PMID20724987). Using these model systems, we are defining MLL1-dependent transcriptional networks, how they support hematopoietic development, how they differ from leukemogenic programs, and whether they can be exploited to alter stem cell functions.