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/enhancer-binding protein (C/EBP)α 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/EBPα and interaction of PU.1 with c-Jun elevates PU.1 activity. Zippering of C/EBPα 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/EBPɛ direct granulopoiesis. Both C/EBPα and RARs induce C/EBPɛ, 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-κB directly binds and cooperates with C/EBPβ to induce the inflammatory response in mature myeloid cells and potentially also cooperates with C/EBPα to regulate early myelopoiesis.
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AF is supported by the National Institutes of Health, the Samuel Waxman Cancer Research Foundation, and the Children's Cancer Foundation.
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Friedman, A. Transcriptional control of granulocyte and monocyte development. Oncogene 26, 6816–6828 (2007). https://doi.org/10.1038/sj.onc.1210764
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