Transcriptional control of granulocyte and monocyte development

AD Friedman - Oncogene, 2007 - nature.com
AD Friedman
Oncogene, 2007nature.com
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 …
Abstract
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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