Transcriptional regulation of myelopoiesis. (A) Model for the transcriptional regulation of commitment to the granulocytic and monocytic lineages. Arrows represent stimulation and the perpendicular bar indicates inhibition. C/EBP or PU.1 commit pluripotent hematopoietic stem cells (PHSC) to CFU-GM. C/EBP may modestly induce PU.1 in these cells. Increased activity of C/EBP stimulates granulopoiesis, with further induction of PU.1, and may inhibit monocyte development.25 PU.1 is required for terminal monocyte differentiation and is also required for B-lymphoid development. (B) Model for the transcriptional program regulating granulopoiesis in committed progenitors. G-CSF activates several signal transduction pathways that allow cell proliferation and stimulate differentiation, including the Ras/MAPK pathway, the Jak/Stat pathway, and induction of c-Myc. The CBF and c-Myb transcription factors also stimulate proliferation. Removal of IL-3 signals, addition of G-CSF signals, or both lead to elevated C/EBP levels, a phenomenon inhibited by bcr/abl. C/EBP induces increased levels of PU.1 and, together with CBF and c-Myb, these factors then activate early markers of myeloid differentiation, including the MPO and NE genes. C/EBP also leads to a delayed increased in p27^Kip1, in cooperation with Stat3 and other factors. p27 in turn induces Rb hypophosphorylation and a G1/S arrest. Hypophosphorylated Rb, PU.1, and several other transcription factors expressed, activated, or inactivated at a later stage in granulopoiesis (eg, C/EBPβ, C/EBPɛ, Sp1, RAR, and loss of CDP) may then induce late differentiation markers, such as the LF gene and genes required to induce the neutrophilic morphology.