Transcriptional regulation of granulocyte and monocyte development

Granulocytes and monocytes develop from a common myeloid progenitor. Early granulopoiesis requires the C/ EBPalpha, PU.1, RAR, CBF, and c-Myb transcription factors, and terminal neutrophil differentiation is dependent upon C/EBPepsilon, PU.1, Sp1, CDP, and HoxA10. Monopoiesis can be induced by Maf-B, c-Jun, or Egr-1 and is dependent upon PU.1, Sp1, and ICSBP. Signals eminating from cytokine receptors modulate factor activities but do not determine cell fates. Orchestration of the myeloid developmental program is achieved via cooperative gene regulation, via synergistic and inhibitory protein-protein interactions, via promoter auto-regulation and cross-regulation, via regulation of factor levels, and via induction of cell cycle arrest: For example, c-Myb and C/EBPalpha cooperate to activate the mim-1 and NE promoters, PU.1, C/EBPalpha,, and CBF, regulate the NE, MPO, and M-CSF Receptor genes. PU.1:GATA-1 interaction and C/EBP suppression of FOG transcription inhibits erythroid and megakaryocyte gene expression. c-Jun:PU.1, ICSBP:PU.1, and perhaps Maf:Jun complexes induce monocytic genes. PU.1 and C/EBPa activate their own promoters, C/EBPalpha rapidly induces PU.1 and C/EBPepsilon RNA expression, and RARalpha activates the C/ EBPepsilon promoter. Higher levels of PU.1 are required for monopoiesis than for B-lymphopoiesis, and higher C/ EBP levels may favor granulopoiesis over monopoiesis. CBF and c-Myb stimulate proliferation whereas C/EBPa induces a G1/S arrest; cell cycle arrest is required for terminal myelopoiesis, perhaps due to expression of p53 or hypo-phosphorylated Rb.