¹Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA

Correspondence: Dr AD Friedman, Division of Pediatric Oncology, Johns Hopkins University, Cancer Research Building I, Room 253, 1650 Orleans Street, Baltimore, MD 21231, USA. E-mail: afriedm2@jhmi.edu

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) 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 and interaction of PU.1 with c-Jun elevates PU.1 activity. Zippering of C/EBP 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 direct granulopoiesis. Both C/EBP and RARs induce C/EBP, 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-B directly binds and cooperates with C/EBP to induce the inflammatory response in mature myeloid cells and potentially also cooperates with C/EBP to regulate early myelopoiesis.