Gfi1, a transcriptional repressor, is critically required for hematopoietic stem cell (HSC) self-renewal and normal myeloid differentiation. Humans with severe congenital neutropenia (SCN) display mutations in Gfi1 (encoding GFI1N382S), and previous work in our lab has shown that this mutant acts as a dominant negative block to granulopoiesis (Immunity, 2008; PMID:18328744). Gfi1 regulation of HoxA9, Pbx1 and Meis1 underlies these phenomena in that the Gfi1 / Hox transcriptional circuit controls the accumulation of myeloid progenitors in vivo (Blood, 2009; PMID:19346496). Additionally, we have shown that Gfi1 regulates microRNAs (miRs) during myelopoiesis, and that the forced expression of miRs in bone marrow cells results in an accumulation of myeloid progenitors similar to that of Gfi1 (Blood, 2009; PMID: 19278956). We are investigating the role of microRNA targets in stem cells and myeloid biology, as well as investigating whether miRs represent potential therapeutic targets for clinical intervention in diseases such as SCN and leukemia.