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CONCISE REVIEW |
in the Terminal Stages of Granulocyte Differentiation
The Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Key Words. Neutrophil • Myelopoiesis • Transcription • Hematopoiesis • Granulopoiesis
Julie A. Lekstrom-Himes, M.D., Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, 11N103, Bethesda, Maryland 20892, USA. Telephone: 301-402-9139; e-mail: jlekstrom{at}atlas.niaid.nih.gov
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ABSTRACT |
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 Top Abstract IntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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, has been identified as a critical regulator of terminal granulopoiesis and one of the causative mutations in the human disease, neutrophil-specific granule deficiency. C/EBPs are a family of transcription factors sharing numerous structural and functional features and to date include C/EBP
, -ß, -
, -
, -, and –
.
C/EBP was the first family member isolated and characterized, its essential role in hepatocyte and adipocyte differentiation demonstrated in knockout mouse models. Subsequent analysis of the hematopoietic elements in fetal mouse liver revealed its critical role in myelopoiesis.
Understanding the role of C/EBP in terminal granulopoiesis in the context of other known transcription factors is ongoing with analysis of deficient and conditionally expressing cell lines and knockout models. Mouse models with targeted gene disruptions have contributed greatly to our understanding of the transcriptional regulation of granulopoiesis. Further manipulation of these models and other conditional expression systems have bypassed some of the limitations of knockout models and helped delineate the interactions of different transcription factors in affecting granulocyte development. Phenotypic expression of the loss of C/EBP in mice is extreme, resembling absolute neutropenia with systemic infection with P. aeruginosa. Future work will need to explore the regulation of C/EBP expression, its functional interactions with other transcriptional regulators such as PU.1, and its role in monocyte differentiation and function in the mouse.
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INTRODUCTION |
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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. As a consequence of its characterization, using both in vitro and knockout mouse models, C/EBP has been identified as a critical regulator of terminal granulopoiesis and one of the causative mutations in the human disease, neutrophil-specific granule deficiency. |
TRANSCRIPTIONAL REGULATORS OF GRANULOPOIESIS |
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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). Core-binding factors (CBFs), CCAAT/enhancer binding proteins such as C/EBP, c-Myb, and Ets factors are key transcriptional regulators of granulopoiesis [1-3], beginning with the commitment of hematopoietic progenitors and progressing through the stages of early then terminal differentiation. CBF family member CBF2, or AML1, is critical for commitment of hematopoietic stem cells to lymphoid and myeloid progenitors [4]. Targeted disruption of AML1 in mice, as well as its DNA-binding partner, CBFß, results in gestational intrauterine death on gestational day 11-12.5 due to hemorrhage and a profound lack of liver hematopoietic elements [5-9]. Acting downstream and in conjunction with the CBFs is C/EBP, a member of the C/EBP family. C/EBP is highly expressed in myeloblasts and decreases with myeloid differentiation, supporting its role in early myeloid progenitors [10]. Coexpression of C/EBP with CBFs and PU.1, a member of the Ets family of transcription factors, induces transactivation of a number of myeloid-specific genes including primary granule protein neutrophil elastase and myeloperoxidase, GM-CSF receptor, macrophage-CSF (M-CSF) receptor, and G-CSF receptor [11-14]. Also essential to early events in granulopoiesis is c-Myb and myeloid zinc finger protein (MZF)-1. c-Myb knockout mice lack all hematopoietic lines, with the exception of megakaryocytes; however, ectopic expression of c-Myb in the promyelocytic cell line 32Dcl3 permits G-CSF induction of primary granule protein myeloperoxidase despite no further evidence of terminal differentiation [15, 16]. MZF-1 transactivates the myeloperoxidase, lactoferrin, and CD34 promoters, whereas deficient expression, secondary to antisense oligonucleotides, decreases G-CSF-driven granulocyte colony formation from bone marrow progenitors [17, 18].
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. Early events in granulopoiesis are unaffected by PU.1 deficiency including myeloperoxidase and G-CSF receptor expression; however, PU.1-deficient myeloid cells fail to express markers of granulocyte maturity such as CD11b and CD64 [19]. Sp1 is also essential for CD11b expression [20]. CDP, homologous to the Drosophila cut protein, binds negative regulatory elements in genes expressed late during granulopoiesis including the cytochrome b heavy chain (gp91phox) of the NADP reduced (NADPH) oxidase enzyme, lactoferrin, and neutrophil collagenase, downregulating their expression [21-24]. Various homeobox proteins act during both early and late granulopoiesis. HoxA9, HoxA10, and HoxA5 are expressed early during myelopoiesis, with aberrant expression affecting overall granulocyte numbers [25-27]. Hlx and HoxB7 act reciprocally on terminal granulopoiesis; Hlx induces granulocyte maturation and HoxB7 inhibits differentiation [28, 29]. The retinoblastoma protein may be involved in monocytic versus granulocytic lineage determination, in conjunction with its interactions with C/EBPß and PU.1 [2]. Also, binding of RAR with all-trans retinoic acid induces expression of Hox and STAT proteins and the induction of remission in patients with acute promyelocytic leukemia [2, 30].
Necessary for understanding the context of C/EBP in terminal granulopoiesis is an appreciation of the functional aspects of differentiation including the generation of granule matrix and surface proteins. Neutrophil granule proteins are transcriptionally regulated and expressed during specific stages of granulopoiesis [31]. Primary or azurophil granule proteins are synthesized early, during the myeloblast to promyelocyte transition, and are easily identified upon Giemsa-Wright staining of promyelocytes as large azurophil granules [31]. Specific granule proteins are generated during the promyelocyte to myelocyte transition of myelopoiesis, as are defensins; however, defensins are specifically targeted to primary granules following release from the trans-golgi network [31]. Gelatinase granules are similar to specific granules, however, synthesis occurs later, during the metamyelocyte to band transition, and they are considered by some to be a subset of specific granules [31]. Finally, secretory vesicles are highly mobilized granules that carry a high density of membrane receptors including CD11b, CD14, CD16, and formyl peptide receptors [31]. They are synthesized late during myelopoiesis, however, the mechanism of formation is not known.
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THE C/EBP FAMILY OF TRANSCRIPTION FACTORS |
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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, -ß, -, -, -, and -. The prototypic C/EBP is a modular protein, containing a carboxy-terminal leucine-zipper dimerization domain, a DNA-binding domain, and an N-terminal activation domain (Fig. 2A) [32]. Dimerization via the leucine zipper region, with homo-or heterotypic C/EBPs or other transcription factors is a prerequisite for DNA binding and subsequent gene transactivation [33]. All C/EBPs, with the exception of C/EBP, are expressed in multiple cell types; however, protein levels vary with developmental- and tissue-specificity [32]. Messenger RNAs for C/EBP and C/EBPß encode multiple protein isoforms, translated by a leaky ribosomal scanning mechanism [34, 35]. The full-length isoforms contain complete transactivating elements, while the shorter isoforms retain only the dimerization and DNA-binding domains. Consequently, protein expression of the truncated isoforms modulate the transactivating capacities of the full-length proteins by both competing for cognate DNA binding sites, as well as, dimerizing with and attenuating the function of the full-length proteins.
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was the first family member isolated and characterized, its essential role in hepatocyte and adipocyte differentiation demonstrated in knockout mouse models [36, 37]. Subsequent analysis of the hematopoietic elements in fetal mouse liver revealed its critical role in myelopoiesis. C/EBP-deficient mice fail to undergo myeloid differentiation beyond the myeloblast stage and do not express receptors for G-CSF or interleukin 6 (IL-6) [38, 39]. Additionally, C/EBP-deficient mice do not respond to in vivo delivery of G-CSF, nor develop granulocytic colony-forming units in vitro [38]. Retroviral rescue of the G-CSF receptor or IL-6 receptor in C/EBP-deficient progenitors restores granulopoiesis [39]. Interestingly, C/EBP-deficient progenitors will differentiate into granulocytes in response to IL-3 and GM-CSF; however, because IL-3 and GM-CSF are not normally found in the bone marrow, nor cross the placental barrier, normal granulopoiesis is not seen in vivo in C/EBP knockout mice [39]. |
CEBP
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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in myeloid differentiation is the most recently cloned member of the C/EBP family, C/EBP (chr. 14q11.2) [40-42]. Unlike other C/EBPs, C/EBP is expressed only in myeloid lineages, with some low but detectable expression in the lymphoblastic cell line MOLT4 and the ovaries [41, 43]. Also dissimilar with other human C/EBPs, varying sized C/EBP protein isoforms, 32 kDa, 30 kDa, 27 kDa, and 14 kDa, are translated from different mRNA isoforms rather than from a single mRNA as seen with C/EBP and C/EBPß (Fig. 2B
) [43]. Bone marrow RNA blotting reveals that the predominant C/EBP mRNA isoform is approximately 1.4 kB, consistent with findings from bone marrow cDNA library analysis [41, 43]. Alternatively, neutrophil RNA blotting shows that the predominant C/EBP mRNA isoform is approximately 2.4 kB, again consistent with findings from a neutrophil cDNA library [41, 43]. Analysis of the genomic and complementary RNA sequences reveals differential promoter use in the generation of these mRNAs; however, the functional significance of these promoters has not been explored [43]. While both the 1.4 kB and 2.4 kB mRNA isoforms encode the full-length 32-kDa C/EBP protein, an additional 1.3 kB mRNA, detected in 5' RACE products from HL60 mRNA, encodes the 14-kDa truncated protein of C/EBP [43]. This shorter isoform was not found in bone marrow cDNA libraries and is driven by the same promoter as the 2.4 kB neutrophil mRNA isoform [43]. The 27-kDa isoform was detected using 5' RACE analysis of HL60 RNA, and its functional significance is not known [43]. The 30-kDa isoform differs from the full-length C/EBP by the loss of the N-terminal 32 amino acids [42]. Analysis of GAL4-C/EBP fusion proteins reveals that the transcriptional activation domain lies in the first 18 amino acids, with potent repression elements lying downstream between amino acids 116 and 162 [44]. The truncated 30-kDa isoform reflects this finding, demonstrating reduced transactivating capabilities compared with the full-length 32-kDa C/EBP [45]. In vitro transactivating experiments show that the 32-kDa C/EBP is capable of transactivating the G-CSF recepter and lactoferrin promoters [43, 46]. Analogous with C/EBP and C/EBPß, the shorter, 14-kDa isoform of C/EBP lacks transactivating potential in in vitro reporter assays, compared with the full-length forms of C/EBP or C/EBP in similar experiments [43]. It is hypothesized that similar to the truncated isoforms of C/EBP and C/EBPß, the 14-kDa isoform of C/EBP may attenuate the transcriptional activation of the full-length C/EBP [43]. Despite the identification of four different-sized C/EBP isoforms, RNA expression levels predict that the predominant form in bone marrow is the full-length protein, which possesses the greatest transactivating potential among all of the isoforms.
C/EBP is highly conserved between human and rodents [47]. Genomic and mRNA analysis of murine C/EBP (chr. 14q11.2) reveals that the full-length murine 34-kDa protein is transcribed from a single 1.3 kB mRNA isoform expressed primarily in myeloid lineages [47]. Functional analysis of GAL4 protein fusion products demonstrates the presence of two transcriptional activation domains as well as two repressor domains in its N-terminal regions [48]. Ectopic expression of murine C/EBP in the murine B lymphoblastic cell line P388 induces expression of MCP-1 and IL-6 with lipopolysaccharide exposure, as well as increased basal levels of chemokines macrophage inflammatory protein (MIP)-1 and MIP-1ß [47]. Induction of the M-CSF receptor with C/EBP expression in these cells also suggests a role for C/EBP in macrophage development and function [47]. Likewise, representational difference analysis of thioglycollate-induced neutrophils and macrophages from C/EBP-deficient mice detects predominantly macrophage-expressed genes including cathepsin L, MIP-1, MCP-3, and galactose/N-acetylgalactosamine-specific lectin [49]. C/EBP induction of monocyte-specific genes may represent a divergence between the role of C/EBP in humans and rodents—monocytic differentiation of human bipotent cell lines such as HL60, U937, and NB4 results in reduced C/EBP mRNA expression, and granulocytic differentiation produces increased expression [42, 43]. In rodents, however, C/EBP may have a role in monocytic differentiation and function.
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C/EBP-DEFICIENT MICE
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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gene in mice was accomplished by homologous recombination of the second exon containing the leucine zipper and DNA-binding domain with the PGKneo gene [50]. C/EBP nullizygous offspring are normal at birth and fertile, however, they fail to produce normal neutrophils or eosinophils [50]. Peripheral blood and bone marrow neutrophils in deficient mice are easily distinguished by Giemsa-Wright staining by their atypical nuclear morphology compared with wild-type neutrophils (Fig. 3) [50]. Eosinophils are not detectable with Giemsa-Wright staining [50]. Median survival of C/EBP-deficient mice is 50 to 75 days with the usual cause of death due to opportunistic infection with Pseudomonas aeruginosa and tissue destruction [50]. Hematological parameters show no differences between platelet counts or red blood cell numbers [50]. Additionally, peripheral blood white cell differentials in young mice (two weeks of age or less) show only a slight increase in less mature myeloid cells in knockout animals compared with wild-type mice [50]. Conversely, older mice (three to four months of age) display a pronounced increase in immature myeloid forms in both their peripheral blood and bone marrow [50]. Knockout mice maintained in a germ-free environment or with antibiotic ementation show a prolonged life span with no detectable increase in malignancy rates compared with wild type mice (unpublished observations).
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-deficient granulocytes reveals numerous functional abnormalities [50, 51]. Generation of hydrogen peroxide by phorbol-myristate 13-acetate stimulation is vastly diminished in C/EBP-deficient neutrophils, as measured for fluorescence of dihydrorhodamine and flow cytometry [50]. Despite the apparent loss of NADPH oxidase activity in these neutrophils, subsequent RNA blotting demonstrates detectable levels of the oxidase components in C/EBP-deficient cells, suggesting that the lack of C/EBP expression does not directly affect the transcription of oxidase components [46]. An alternative explanation for this defect became apparent with the failure to detect secondary or tertiary granule proteins in C/EBP knockout neutrophils. Secondary and tertiary granules maintain a reservoir of the membrane-bound elements of the NADPH oxidase apparatus [31]. Neutrophil activation by ß-integrin binding results in translocation of secondary and tertiary granule membranes to the cell surface and secretion of contents into the extracellular space [31]. Loss of this reservoir of oxidase components cripples the oxidative response of the C/EBP-deficient neutrophil.
Additionally, the lack of expression of secondary and tertiary granule protein mRNAs in C/EBP-deficient neutrophils may reflect the direct loss of the transcriptional activation of C/EBP. Blotting of RNA from C/EBP-deficient bone marrow demonstrates specific loss of lactoferrin and gelatinase B, with normal to elevated expression of primary granule proteins neutrophil elastase, myeloperoxidase, and proteinase-3 [51]. Lysozyme M, contained both in primary and secondary granules, is present in C/EBP-deficient bone marrow [51]. Subsequent work has shown that C/EBP directly transactivates the murine lactoferrin promoter [46].
C/EBP deficiency results in other granulocyte defects including delayed migration in response to an in vivo inflammatory challenge and impaired bacteriocidal responses [51]. Analysis of neutrophil migration in response to intraperitoneal thioglycollate injection shows an initial delay in neutrophil egress, which normalizes within 24 h [51]. This response likely reflects the loss of secondary and tertiary granules that provide an intracellular reserve of ß-integrins for rapid upregulation in response to granulocyte activation. Additionally, diminished bacterial killing is detectable using an in vitro staphylococcal killing assay [51]. These results, which show a subtle, however, significant decrease in bactericidal activity, are similar to those measured in NADPH oxidase component p47-deficient mice and may reflect the functional importance of the respiratory burst in phagosomal killing of intracellular bacteria [52].
Importantly, phenotypic analysis of the C/EBP-deficient mouse does not resemble the NADPH oxidase-deficient mouse models, despite the profound loss of oxidase activity. NADPH oxidase p47- and p91-deficient mice survive longer than C/EBP knockout mice, succumbing to catalase-positive bacterial and fungal pathogens [52, 53]. The observation that C/EBP-deficient mice failed to transactivate secondary granule protein genes provided the critical clue to determining one of the genetic defects seen in the human disease, neutrophil-specific granule deficiency.
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NEUTROPHIL-SPECIFIC GRANULE DEFICIENCY |
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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-granule fibronectin and fibrinogen and decreased surface expression of high molecular weight von Willebrand factor [57]. Involvement of multiple myeloid lineages suggests an underlying defect in myelopoeisis. Importantly, patient neutrophils lack lactoferrin, a neutrophil-specific granule marker, despite normal levels of lactoferrin in patient salivary glands, suggesting a defect in transcriptional regulation of myeloid cell granule proteins [58].
Given the striking similarities between the phenotype of the C/EBP knockout mouse and patients with neutrophil-specific granule deficiency, the genomic sequence of the C/EBP gene was sequenced in a patient and found to contain a 5' base pair deletion in the second exon [59]. Subsequent transcription from this homozygous deletion results in a transcript with a premature termination codon and loss of the full-length C/EBP isoform, as shown in RNA and protein blotting of the patient's bone marrow [59]. Recently, a second recessive frame-shift mutation was identified in another patient with neutrophil-specific granule deficiency, resulting in loss of C/EBP expression [60]. Several other patients with specific granule deficiency, however, demonstrate no detectable mutations in the C/EBP genomic locus (Gallin and Lekstrom-Himes, unpublished observations), suggesting genetic heterogeneity of the underlying mutations.
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THE ROLE OF C/EBP IN THE TERMINAL DIFFERENTIATION OF GRANULOCYTES
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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in terminal granulopoiesis in the context of other known transcription factors is ongoing with analysis of deficient and conditionally expressing cell lines and knockout models. C/EBP, acting upstream of C/EBP, is a critical factor for the myeloblast to promyelocyte transition. Conditional expression of C/EBP in a bipotential hematopoietic cell line induces granulocytic differentiation, G-CSF receptor expression, and blocks monocytic differentiation [61]. Additionally, C/EBP expression in cell lines or in 32Dcl3 cells induces expression of C/EBP and transcription of PU.1 and secondary granule protein lactoferrin [61, 62]. Likewise, expression of C/EBP in bipotential hematopoietic cell lines is induced with granulocytic differentiation and decreased with monocytic differentiation [63].
Despite the terminal functional defects in C/EBP-deficient neutrophils, the loss of secondary and tertiary granule proteins pinpoints its temporal role to the promyelocytic-myelocytic stage of granulocyte development. Analysis of bone marrow colony-forming units from C/EBP-deficient precursors corroborates these findings, showing an apparent block in in vitro differentiation at the promyelocyte stage (Fig. 3) [50]. C/EBP interacts with the DNA-binding domain of c-Myb, synergistically upregulating expression of early myeloid specific proteins mim-1, neutrophil elastase, and G-CSF receptor [45]. Furthermore, C/EBP may be the responsible target gene of retinoic acid-induced differentiation of acute promyelocytic leukemia cells [64]. The presence of a retinoic acid response element in the promoter of C/EBP and its selective upregulation with all-trans retinoic acid treatment in cell lines expressing the promyelocytic leukemia/retinoic acid receptor protein suggests that C/EBP may transduce the differentiating signals in promyelocytic cells treated with retinoic acid.
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CONCLUSION |
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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and examination of its role in knockout models and conditional cell lines demonstrates its critical involvement in the promyelocyte to myelocyte transition. Unsuccessful differentiation beyond this stage, as shown in the knockout mouse, has profound effects upon multiple aspects of granulocyte function, including bactericidal killing and the oxidative burst. Phenotypic expression of the loss of C/EBP in mice is extreme, resembling absolute neutropenia with systemic infection with P. aeruginosa. Interestingly, the phenotypic consequences of C/EBP mutation in humans are not nearly as severe, again supporting an expanded role for C/EBP in murine myelopoiesis or alternatively, indicating a lack of redundant systems in the mouse. Future work will need to explore the regulation of C/EBP expression, its functional interactions with other transcriptional regulators such as PU.1, and its role in monocyte differentiation and function in the mouse.
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ACKNOWLEDGMENTS |
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TopAbstractIntroductionTranscriptional Regulators of...The C/EBP Family of...CEBP{varepsilon}C/EBP{varepsilon}-Deficient MiceNeutrophil-Specific Granule...The Role of C/EBP{varepsilon}...ConclusionReferences |
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REFERENCES |
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