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Transcriptional Regulation of Granulocyte and Monocyte Development Oncogene (2002) 21, 3377 ± 3390 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Transcriptional regulation of granulocyte and monocyte development Alan D Friedman*,1 1Division of Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland, MD 21231, USA Granulocytes and monocytes develop from a common granulocyte/macrophage progenitors (GMPs), charac- myeloid progenitor. Early granulopoiesis requires the C/ terized by expression of CD34 and Fcg Receptor(II/III) EBPa, PU.1, RAR, CBF, and c-Myb transcription (Akashi et al., 2000; Traver et al., 2001). These factors, and terminal neutrophil dierentiation is progenitors in turn give rise to granulocyte-, mono- dependent upon C/EBPe, PU.1, Sp1, CDP, and cyte-, and granulocyte/monocyte-colony forming units HoxA10. Monopoiesis can be induced by Maf-B, c- (CFU-G, CFU-M, and CFU-GM). Granulocyte-Col- Jun, or Egr-1 and is dependent upon PU.1, Sp1, and ony Stimulating Factor (G-CSF) enables the formation ICSBP. Signals eminating from cytokine receptors of CFU-G in methylcellulose cultures, Macrophage- modulate factor activities but do not determine cell Colony Stimulating Factor (M-CSF, CSF-1) enables fates. Orchestration of the myeloid developmental the growth of CFU-M, and Granulocyte/Macrophage- program is achieved via cooperative gene regulation, Colony Stimulating Factor (GM-CSF) or Interleukin-3 via synergistic and inhibitory protein ± protein interac- (IL-3) enable the proliferation of CFU-G, CFU-M, tions, via promoter auto-regulation and cross-regulation, and CFU-GM. In addition to these features of normal via regulation of factor levels, and via induction of cell cells, the ®nding that a common subset of acute cycle arrest: For example, c-Myb and C/EBPa myeloid leukemia has both a granulocytic and cooperate to activate the mim-1 and NE promoters, monocytic cellular component further underscores the PU.1, C/EBPa, and CBF, regulate the NE, MPO, and close developmental relationship of neutrophils and M-CSF Receptor genes. PU.1:GATA-1 interaction and monocytes. Fetal liver and adult marrow also contain C/EBP suppression of FOG transcription inhibits progenitors capable of producing B-lymphoid and erythroid and megakaryocyte gene expression. c-Jun:- macrophage cells in single colonies, re¯ecting both PU.1, ICSBP:PU.1, and perhaps Maf:Jun complexes the plasticity of pluripotent stem cell commitment and induce monocytic genes. PU.1 and C/EBPa activate the relatedness of these lineages (Lacaud et al., 1998; their own promoters, C/EBPa rapidly induces PU.1 and Montecino-Rodriguez et al., 2001; Traver et al., 2001). C/EBPe RNA expression, and RARa activates the C/ Monocyte progenitors not only develop into macro- EBPe promoter. Higher levels of PU.1 are required for phages but are also capable of osteoclast dierentiation monopoiesis than for B-lymphopoiesis, and higher C/ (Roodman, 1996), and GMPs share with common EBP levels may favor granulopoiesis over monopoiesis. lymphoid progenitors (CLPs) the capacity to generate CBF and c-Myb stimulate proliferation whereas C/EBPa myeloid dendritic cells (Manz et al., 2001). induces a G1/S arrest; cell cycle arrest is required for Neutrophil maturation proceeds from the myeloblast terminal myelopoiesis, perhaps due to expression of p53 to the promyelocyte, when primary granules become or hypo-phosphorylated Rb. apparent, to the myelocyte, when cell division ceases Oncogene (2002) 21, 3377 ± 3390. DOI: 10.1038/sj/ and secondary or speci®c granules begin to appear, to onc/1205324 the metamyelocyte, band, and ®nally the neutrophil, which has a three-lobed nucleus and tertiary granules. Keywords: granulocyte; monocyte; dierentiation; Early markers of granulopoiesis include the G-CSF C/EBP; PU.1 Receptor, the CD33 and CD13 surface markers, and primary granule components, such as myeloperoxidase (MPO), neutrophil elastase (NE), myeloblastin (MBN), Introduction lysozyme and avian mim-1. Oxidation system compo- nents, such as the gp91-phox cytochrome heavy chain, Polymorphonuclear and mononuclear phagocytes func- are expressed from the myelocyte stage onward and tion in host defense against infections and are capable later markers of neutrophil development include of recognizing, ingesting, and destroying foreign secondary granule components, such as lactoferrin materials and organisms. Pluripotent hematopoietic (LF) and neutrophil gelatinase (NG), and the Gr-1 stem cells in fetal liver or in adult marrow give rise to surface marker. Monopoiesis proceeds from the monoblast to the circulating monocyte, which matures without prolifera- tion to the tissue macrophage. Early markers of this *Correspondence: AD Friedman, Johns Hopkins University, Cancer Research Building, Room 253, 1650 Orleans Street, Baltimore, lineage include the M-CSF Receptor, lysozyme, and Maryland, MD 21231; E-mail: [email protected] the Fcg Receptor(II/III), and latter markers include Regulation of granulopoiesis and monopoiesis AD Friedman 3378 gp91-phox, and several surface proteins: Macrosialin, Table 1 Transcription factors regulating granulocytic or monocytic scavenger receptor (SR), F4/80, CD14, CD11b, and genes CD18. Fcg Receptor(II/III) is also expressed on Gene Transcription factors myeloid progenitors (Carlsson et al., 1995); the Immature granulocytes CD11b:CD18 integrin is also expressed on neutrophils, mim-1 C/EBP's, c-Myb B-lymphocytes, and some T-cell subsets (Christensen et Myeloperoxidase (MPO) C/EBPs, PU.1, CBF, c-Myb, CDP/HoxA10 al., 2001); and CD14 is also expressed in hepatocytes Neutrophil elastase (NE) C/EBPs, PU.1/GABP, CBF, c-Myb, Sp1 (Hetherington et al., 1999). Phagocytic capacity is an Myeloblastin (MBN) C/EBPs, PU.1, c-Myb G-CSF receptor C/EBPs, PU.1 additional hallmark of maturing monocytes. GM-CSF receptor C/EBPs, PU.1 CD13 c-Myb, Ets-1 or Ets, c-Maf Lysozyme C/EBPs, PU.1 Receptor signaling c-fes PU.1, Sp1 Mature granulocytes gp91phox PU.1, ICSBP, CDP, HoxA10 We have recently reviewed how G-CSF Receptor Lactoferrin (LF) C/EBPs, Sp1, CDP signals might modulate granulopoiesis (Ward et al., Immature monocytes 2000). Redundancy of receptor signaling is evident M-CSF receptor C/EBPs, CBF, PU.1, c-Jun from the ®nding that G-CSF (7/7), G-CSF; GM- Lysozyme C/EBPs, PU.1 Mature monocytes CSF (7/7; 7/7); G-CSFR (7/7), or G-CSFR; IL- Macrosialin PU.1, c-Jun 6 Receptor (7/7; 7/7) mice have only about a Scavenger receptor PU.1, c-Jun twofold reduction in marrow neutrophils (Lieschke et CD14 C/EBPs, Sp1 al., 1994; Liu et al., 1996a, 1997; Seymour et al., 1997). gp91phox PU.1, ICSBP, CDP, HoxA10 CD11b PU.1, Sp1 Bcl-2 did not replace G-CSF receptor signals during CD18 PU.1, GABP, Sp1 32D cl3 maturation-MPO and Cathepsin G induction did not occur, but nuclear morphologic changes were observed (Rodel and Link, 1996). Thus, G-CSF receptor signals provide more than a survival function insights gained from characterizing transcription factor in this setting. Similarly, G-CSF receptor signals expression patterns, the phenotypes of knockout mice, cooperated with exogenous C/EBPa to allow induction and the eects of factor over-expression. of MPO and NE in Ba/F3 lymphoid cells and were The promoter of the avian mim-1 promoter is required for induction of C/EBPe in 32D cl3 cells activated cooperatively by C/EBPs and c-Myb in (Wang et al., 2001; Nakajima and Ihle, 2001). Also, immature granulocytic cells (Ness et al., 1993). This introduction of exogenous GM-CSF or IL-2 receptors section will not refer to individual C/EBPs, as C/EBP allows CLPs to be redirected to the granulocyte and family members bind a common DNA motif and often monocyte lineages (Kondo et al., 2000). activate reporter constructs similarly in transient M-CSFR signaling has also recently been reviewed assays. The MPO promoter region is activated (Bourette and Rohrschneider, 2000). Transgenic ex- cooperatively by CBF and c-Myb (Suzow and Fried- pression of bcl-2 in monocytes enabled M-CSF (7/7) man, 1993; Nuchprayoon et al., 1994; Britos-Bray and mice to develop macrophages (Lagasse and Weissman, Friedman, 1997), and its distal enhancer is regulated by 1997). While this ®nding precludes an absolute C/EBPs and PU.1 (Ford et al., 1996). The NE requirement for M-CSF Receptor signals in macro- promoter is regulated cooperatively by C/EBPs, PU.1, phage development, redundant signals available from a and c-Myb; the murine but not the human NE subset of other cytokine receptors may be necessary. promoter is activated weakly by CBF; GABP can The ability of phorbol esters to induce monocytic substitute for PU.1 to cooperatively active the NE dierentiation of hematopoietic cell lines via activation promoter; and a 76 kb NE enhancer is activated by of protein kinase Ca (PKCa) or PKCd suggests that Sp1 and an Ets family member other than PU.1 this signaling pathway is important in normal mono- (Nuchprayoon et al., 1994; 1997, 1999; Oelgeschlager et poiesis (Mischak et al., 1993). Overall, with possible al., 1996). MBN and azurocidin are serine proteases notable exceptions, signals eminating from cytokine highly related to NE. Their promoters contain receptors appear to modulate but not determine sequences elements homologous to the NE elements myeloid dierentiation. which bind C/EBPs, PU.1, and c-Myb (Friedman, 1996a), and indeed these proteins regulate the MBN promoter (Lutz et al., 2001). The promoters of both Regulation of gene expression the G-CSF and GM ± CSF receptor genes are activated by C/EBPs and PU.1 (Hohaus et al., 1995; Smith et al., Dierentiation is de®ned by gene expression patterns, 1996). The CD13 gene is activated directly by c-Myb and so regulatory factors must act either directly or and Ets-1 or Ets-2, and c-Maf indirectly inhibits the indirectly to induce the transcription of lineage transcription of this gene by complexing with c-Myb in markers.
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