Transcriptional control of granulocyte and monocyte development

PU.1 directs the hematopoietic stem cell to the lymphoid-myeloid progenitor ( LMP) and interacts with GATA-binding protein 1 to inhibit commitment to the megakaryocyte-erythroid progenitor. The CCAAT/ enhancerbinding protein ( C/ EBP)alpha then directs the LMP to the granulocyte- monocyte progenitor ( GMP) stage, while inhibiting lymphoid development via cross- inhibition of Pax5 and potentially other regulators. Increased PU. 1 activity favors monocytic commitment of the GMP. Induction of PU.1 by C/EBP alpha and interaction of PU.1 with c-Jun elevates PU. 1 activity. Zippering of C/ EBP alpha with c- Jun or c- Fos also contributes to monocyte lineage specification. An additional factor, potentially an Id1-regulated basic helix - loop - helix protein, may be required for the GMP to commit to the granulocyte lineage. Egr- 1, Egr- 2, Vitamin D Receptor, MafB/ c: Fos and PU. 1: interferon regulatory factor 8 complexes direct further monocytic maturation, while retinoic acid receptor ( RAR) and C/ EBP epsilon direct granulopoiesis. Both C/ EBP alpha and RARs induce C/ EBP epsilon, and PU.1 is also required, albeit at lower levels, for granulocytic maturation. HoxA10 and CAAT displacement protein act as transcriptional repressors to delay expression of terminal differentiation. Gfi-1 and Egr- 1,2/ Nab2 complexes repress each other to maintain myeloid lineage fidelity. NF-kappa B directly binds and cooperates with C/ EBP beta to induce the inflammatory response in mature myeloid cells and potentially also cooperates with C/ EBP alpha to regulate early myelopoiesis.