Regulation Of Myelopoiesis Research Articles

P38MAPK Inhibits Neutrophil Development through Phosphorylation of C/EBPα on Serine 21

Many extracellular stimuli regulate growth, survival and differentiation responses through activation of the dual specificity kinase MAPK kinase 3 (MKK3) and its downstream effector p38 Mitogen-Activated Protein Kinase (MAPK). Using CD34+ hematopoietic progenitor cells, here we describe a novel role for MKK3-p38MAPK in the regulation of myelopoiesis. Inhibition of p38MAPK utilising the pharmacological inhibitor SB203580, enhanced neutrophil development ex-vivo, but conversely reduced eosinophil differentiation. In contrast, constitutive activation of MKK3 dramatically inhibited neutrophil differentiation. Transplantation of β2-microglobulin−/− NOD/SCID mice with CD34+ cells ectopically expressing constitutively active MKK3 resulted in reduced neutrophil differentiation in vivo, whereas eosinophil development was enhanced. Inhibitory phosphorylation of C/EBPα on serine 21 was induced upon activation of p38MAPK. Moreover, ectopic expression of a non-phosphorylatable C/EBPα mutant was sufficient to abrogate MKK3 induced inhibition of neutrophil development. Furthermore, treatment of CD34+ progenitors from patients with severe congenital neutropenia with SB203580 restored neutrophil development. These results establish a novel role for MKK3-p38MAPK in the regulation of lineage choices during myelopoiesis through modulation of C/EBPα activity. This signaling module may thus provide an important therapeutic target in the treatment of bone marrow failure.

219 Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output

219 Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output

Epigenetic Silencing of the Myelopoiesis Regulator microRNA-223 by the AML1/ETO Oncoprotein

Hematopoietic transcription factors are involved in chromosomal translocations, which generate fusion proteins contributing to leukemia pathogenesis. Analysis of patient's primary leukemia blasts revealed that those carrying the t(8;21) generating AML1/ETO, the most common acute myeloid leukemia-associated fusion protein, display low levels of a microRNA-223 (miR-223), a regulator of myelopoiesis. Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation. Here, we identify an additional action for a leukemia fusion protein linking the epigenetic silencing of a microRNA locus to the differentiation block of leukemia.

A Gene Dosage Requirement for Transcription Factor Gfi1 in the Regulation of Myelopoiesis and Myeloproliferative Disorders.

The generation of mature myeloid lineage cells from hematopoietic stem cells (HSCs) requires a precise synergy between cytokine signaling and lineage-specific transcription factors. Gfi1 (Growth Factor Independence 1) is a zinc finger transcription factor that is necessary for normal myelopoiesis. Gfi1 knockout mice display an abnormal ratio of phenotypic common myeloid progenitors (CMP) and granulocyte/monocyte progenitors (GMP), and such mice completely lack mature neutrophils. In contrast, the Gfi1 heterozygote mouse presents no obvious phenotype. Here we show a gene dosage requirement for Gfi1 in the differentiation of mature myeloid cells. While bone marrow from wild type littermates generates granulocytic, monocytic and mixed methylcellulose colonies, Gfi1 knockout bone marrow cells yield mainly monocytic colonies. In comparison to wild type littermates, Gfi1+/− bone marrow cells generate lower numbers of granulocytic colonies and higher numbers of monocytic colonies. Interestingly, methylcellulose colonies from both Gfi1 knockout mice and heterozygotes display increased serial replating capacity in comparison to wild type littermates. These data suggest that Gfi1 gene dosage may control self renewal and may relate to oncogenic transformation. Activating mutations in K-Ras are common genetic abnormalities in human acute myeloid leukemia and myeloproliferative disease (MPD). However, expression of activated Ras from endogenous regulatory sequences (knock-in) results in an MPD of varying lethality. The severity of the K-Ras-induced MPD depends on unknown genetic modifiers, as lethality is increased in a Balb/c genetic background. Given the effect of Gfi1 gene dosage on serial replating, we have analyzed the effect of Gfi1 gene dosage on the activated Ras knock-in mouse model of MPD. Preliminary data indicate that lowering Gfi1 gene dosage modifies the phenotype of activated Ras MPD by dramatically increasing the number of immature circulating myeloid progenitors. These results reveal that Gfi1 is a modifier of Ras induced disease pathogenesis.

The Notch Ligand Jagged1 Causes a Myeloproliferative Disorder in Mice Lacking IκBα.

Hematopoiesis occurs in the liver and the bone marrow during murine development. Newborn mice with a ubiquitous deletion of IκBα develop a severe hematological disorder characterized by an increase of granulocyte/erythroid/monocyte/macrophage colony-forming units (CFU-GEMM) and hypergranulopoiesis. Here, we provide evidence that this particular myeloproliferative disturbance is mediated by continuously deregulated perinatal expression of the Notch ligand Jagged1 in IκBα-deficient hepatocytes. Signaling through Notch-family cell surface receptors and their ligands has been shown to be involved in cell fate decisions of stem cells during hematopoietic/mesenchymal differentiation. However, the role of Notch signaling in myelopoiesis is still under discussion as results gained using different experimental conditions are contradictory. Due to embryonic lethality of Notch1- and Jagged1-deficient mice, alterations of myelopoiesis are difficult to be adressed. In this study, we investigated the function of IκBα and its role within the Jagged/Notch signaling pathway during myelopoiesis. Therefore, a novel mouse line with a conditional (floxed) allele of ikba was established. Ubiquitous deletion of IκBα after cross-breeding with Deleter-Cre mice results in hypergranulopoiesis comparable to the conventional deletion of the allele. A detailed analysis revealed a myeloproliferative syndrome with increased numbers of cycling progenitor cells. The morphological analysis of liver and bone marrow of IκBα-deficient mice showed hypercellularity. The cellular components were dominated by myeloid lineages and represented mostly granulocyts with dysplastic features, characterized by pseudo-Pelger-Huet formation. Myelodysplasia could also be detected in megakaryopoiesis by the presence of micromegakaryocytes. Alterations in erythropoiesis were detectable by condensed chromatin and an asychrony of the nucleocytoplasmic ratio in the red cell precursor population. Together, our results indicate that ubiquitous loss of IκBα results in hypergranulopoiesis progressing to a myelodysplastic syndrome. Systematic analysis of transcription factors, growth factor receptors and NF-κB-regulated cell-survival genes was performed to determine molecular mechanisms underlying hypergranulopoiesis. Our data suggested that Notch1-dependent signals were responsible for the myeloproliferative disorder as Notch1 was upregulated in neutrophils and the Notch ligand Jagged1 in non-hematopoietic cells, namly hepatocytes. Myeloproliferation could be inhibited by blocking the Notch1 ligand Jagged1. Interestingly, deletion of IκBα in neutrophils and macrophages or hematopoietic stem cells did not result in dysregulation of myelopoiesis despite constitutive NF-κB activation in these cells. This establishes the relevance of non-hematopoietic expression of Jagged1 for the control and regulation of myelopoiesis. In summary, we show that cell-fate decisions leading to a premalignant hematopoietic disorder can be initiated by non-hematopoietic cells with inactive IκBα.

Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2

AbstractInhibitor of DNA binding (Id) proteins function as inhibitors of members of the basic helix-loop-helix family of transcription factors and have been demonstrated to play an important role in regulating lymphopoiesis. However, the role of these proteins in regulation of myelopoiesis is currently unclear. In this study, we have investigated the role of Id1 and Id2 in the regulation of granulopoiesis. Id1 expression was initially up-regulated during early granulopoiesis, which was then followed by a decrease in expression during final maturation. In contrast, Id2 expression was up-regulated in terminally differentiated granulocytes. In order to determine whether Id expression plays a critical role in regulating granulopoiesis, Id1 and Id2 were ectopically expressed in CD34+ cells by retroviral transduction. Our experiments demonstrate that constitutive expression of Id1 inhibits eosinophil development, whereas in contrast neutrophil differentiation was modestly enhanced. Constitutive Id2 expression accelerates final maturation of both eosinophils and neutrophils, whereas inhibition of Id2 expression blocks differentiation of both lineages. Transplantation of β2-microglobulin-/- nonobese diabetic severe combined immunodeficient (NOD/SCID) mice with CD34+ cells ectopically expressing Id1 resulted in enhanced neutrophil development, whereas ectopic expression of Id2 induced both eosinophil and neutrophil development. These data demonstrate that both Id1 and Id2 play a critical, although differential role in granulopoiesis.

A preliminary analysis of the goat lactoferrin encoding gene

RiassuntoAnalisi preliminare del gene che codifica la lattoferrina caprina. È stato sequenziato il tratto di DNA comprendente gli ultimi 30 nucleotidi del 2° introne e i primi 52 nucleotidi del 6° introne (per un totale di 2824 bp) del gene della lattoferrina (Lf) di 3 capre appartenenti rispettivamente alla razza Saanen, Maltese e ad una popolazione autoctona allevata in provincia di Catanzaro (Italia). Il confronto tra le sequenze ottenute ha evidenziato 8 siti polimorfici (6 transversioni e 2 transizioni realizzatesi a livello intronico), mentre il confronto con le sequenze dei cDNA della Lf caprina depositate in Banca Dati mostra 5 sostituzioni nucleotidiche responsabili di tre sostituzioni aminoacidiche. In generale, il gene Lf caprino presenta una struttura simile a quella dell’omologo gene nella specie bovina, fatta eccezione per l’inserzione in quest’ultima specie di una sequenza di origine retroposonica (Bov A) a livello del 4° introne.

The Interferon Consensus Sequence-binding Protein Activates Transcription of the Gene Encoding Neurofibromin 1

Deficiency of the interferon consensus sequence-binding protein (ICSBP) is associated with increased myeloid cell proliferation in response to hematopoietic cytokines. However, previously identified ICSBP target genes do not indicate a mechanism for this "cytokine hypersensitivity." In these studies, we identify the gene encoding neurofibromin 1 (Nf1) as an ICSBP target gene, by chromatin immunoprecipitation. Additionally, we find decreased Nf1 expression in bone marrow-derived myeloid cells from ICSBP-/- mice. Since Nf1 deficiency is also associated with cytokine hypersensitivity, our results suggested that NF1 is a functionally significant ICSBP target gene. Consistent with this, we find that the hypersensitivity of ICSBP-/- myeloid cells to granulocyte monocyte colony-stimulating factor (GM-CSF) is reversed by expression of the Nf1 GAP-related domain. We also find that treatment of ICSBP-deficient myeloid cells with monocyte colony-stimulating factor (M-CSF) results in sustained Ras activation, ERK phosphorylation, and proliferation associated with impaired Nf1 expression. These M-CSF effects are reversed by ICSBP expression in ICSBP-/- cells. Consistent with this, we find that ICSBP activates the NF1 promoter in myeloid cell line transfectants and identify an ICSBP-binding NF1 cis element. Therefore, the absence of ICSBP leads to Nf1 deficiency, impairing down-regulation of Ras activation by GM-CSF or M-CSF. These results suggest that one mechanism of increased myeloid proliferation, in ICSBP-deficient cells, is decreased NF1 gene transcription. This novel ICSBP function provides insight into regulation of myelopoiesis under normal conditions and in myeloproliferative disorders.

A new hypothalamic polypeptide is a regulator of myelopoiesis.

The effect of hypothalamic proline-rich polypeptide (PRP) against Pseudomonas aeruginosa infection in BALB/c mice with leukopenia was investigated. Mice were treated with cyclophosphamide (CPA) and were then injected with PRP 24 h after CPA treatment. The lethal doses of P. aeruginosa were injected to mice when the number of peripheral blood leukocytes reached a nadir on day 5 after CPA administration. The administration of PRP significantly increased the survival of infected mice, and had a pronounced protective effect during the period of development of the infection. The number of bacteria in internal organs of PRP-treated mice was significantly lower than that in control mice. In PRP-treated mice, the neutrophil levels in peripheral blood started to increase 7 days after CPA administration and were consistently higher, and they were more mature than those in controls. Our results may indicate the ability of PRP to stimulate recovery of myelopoiesis and enhance mature neutrophil function.

Mice Defective in Two Apoptosis Pathways in the Myeloid Lineage Develop Acute Myeloblastic Leukemia

Fas-deficient (Fas lpr/lpr ) mice constitutively expressing Bcl-2 in myeloid cells by the hMRP8 promoter often develop a fatal disease analogous to human acute myeloblastic leukemia (AML-M2). Hematopoietic cells from leukemic Fas lpr/lpr hMRP8bcl-2 animals form clonogenic blast colonies in vitro and can transfer disease to wild-type mice. In vitro ligation of Fas on Fas +/+ hMRP8bcl-2 marrow cells depletes approximately 50% of myeloid progenitor activity, demonstrating that Bcl-2 can only partially block Fas-mediated death signals in myelomonocytic progenitors. In addition, Fas lpr/lpr marrow contains greatly increased numbers of myeloid colony-forming cells as compared to Fas +/+ controls. Taken together, these data suggest that Fas has a novel role in the regulation of myelopoiesis and that Fas may act as a tumor suppressor to control leukemogenic transformation in myeloid progenitor cells.

Activation of HIV-1 Coreceptor (CXCR4) Mediates Myelosuppression

Chemokines are cytokines that activate and induce the migration of leukocytes. Stroma-derived factor-1 (SDF-1) is a novel chemokine that blocks the entry of T-tropic HIV-1 mediated by fusin/CXCR4/LESTR (leukocyte-derived seven-transmembrane domain receptor). In this work we demonstrate that SDF-1 triggers increases in intracellular calcium and inhibits the proliferation of myeloid progenitor cell line 32D. By contrast, SDF-1 neither triggers a calcium response nor affects the proliferation of the myeloid progenitor cell line 32D-GR that is deficient in CXCR4. Responsiveness to SDF-1 was rescued by transfection of 32D-GR cells with a cDNA encoding the human CXCR4. The data indicate that SDF-1 induces myelosuppression by activation of CXCR4. The constitutive production of SDF-1 by bone marrow stromal cells argues for a major role of SDF-1 on the regulation of myelopoiesis.

Cooperative Interactions between the Amino- and Carboxyl-terminal Lobes Contribute to the Unique Iron-binding Stability of Lactoferrin

Lactoferrin is a member of the transferrin family of iron-binding proteins. Several functions have been ascribed to lactoferrin, including regulation of iron homeostasis, antibacterial properties, and regulation of myelopoiesis. However, the structural features of lactoferrin that are required for most of these functions are unknown. Previously, we reported the development of an efficient fungal expression system to produce recombinant human lactoferrin. The availability of this production system demonstrated the feasibility of producing mutant lactoferrins to address the structure/function relationship of the protein. In the present study, we used a site-directed mutagenesis approach to address the contribution of the bilobal structure of lactoferrin to its unique iron-binding stability. Like transferrin, lactoferrin consists of two repeated iron-binding lobes that bind one iron atom each. However, unlike transferrin, lactoferrin retains iron over a broad pH range, a key property that contributes to the unique iron-binding functions of the protein. Using mutants that selectively ablate the iron-binding function in either lobe, we demonstrate differential iron-binding stability of the amino- and carboxyl-terminal iron-binding lobes of lactoferrin. Further, we show that the unique iron-binding stability of the protein is imparted primarily by the carboxyl-terminal domain which functions cooperatively to stabilize iron-binding to the amino-terminal domain of lactoferrin.

Hemorrhagic Shock Abolishes the Myelopoietic Response to Turpentine-Induced Soft Tissue Injury

Hemorrhagic shock has been shown to alter bone marrow (BM) myelopoiesis. Isolated hemorrhagic shock is uncommon after trauma and the combined effect of tissue injury and shock on myelopoiesis is unknown. We studied the growth of BM granulocyte-macrophage colony forming units (CFU-GM) following shock and soft tissue injury. Rats were anesthetized and allocated into one of four groups: CONTROL, sham neck dissection; SHOCK, rats were bled to a mean BP of 45 mmHG for 45 min and resuscitated with shed blood and saline; TURP, soft tissue injury was induced by turpentine 0.5 ml/100 g SQ into the hindquarter; SHOCK + TURP, rats received TURP just before SHOCK as described above. Groups ( n = 6) were sacrificed 1, 3, and 5 days after treatment. BM cells plated for CFU-GM and splenic macrophages were cultured for IL-1 production. Unstimulated splenic macrophage production of IL-1α was not different for any group except Day 5 turpentine animals. TURP induced a significant increase in CFU-GM on Day 1 compared to that in control (47 ± 22 vs 21 ± 11; P < 0.05). SHOCK completely abolished this response to TURP. Both the SHOCK and TURP alone increased CFU-GM on Day 5 compared to that in CONTROL but there was no additive effect in the SHOCK + TURP group. These data show that the BM response to combined soft tissue injury and shock (TURP + SHOCK) appears similar to that of SHOCK alone and that hemorrhagic shock appears to be a significant immunosuppressive factor in the regulation of myelopoiesis following injury.

Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-acting anti-rheumatic drugs

The pathogenesis of rheumatoid arthritis and the mode of action of anti-rheumatic drugs are unknown. This hypothesis proposes that haemopoietic growth factors (colony stimulating factors [CSFs]) have an important role in rheumatoid arthritis as regulators of myelopoiesis and as activators of inflammatory leucocytes. It also suggests that slow-acting anti-rheumatic drugs may work by inhibiting myelopoiesis. This opposition to one of the actions of the CSFs would result in fewer inflammatory cells in the inflamed joints.

Suppressor cytokines and regulation of myelopoiesis. Biology and possible clinical uses.

A number of biologically active and biochemically well-characterized cytokines have been shown to have either direct or indirect suppressive activities on the proliferation/differentiation of myeloid stem/progenitor cells. This article is a brief review of the actions of some of these molecules. These molecules include H-subunit ferritin, macrophage inflammatory protein-1 alpha, the interferons-alpha, -beta, and -gamma, the tumor necrosis factors-alpha and -beta (lymphotoxin), prostaglandins, E1 and E2, inhibin, transforming growth factor-beta, and lactoferrin. I will also review the actions of other suppressor molecules, including a newly identified 8-kd molecule that has not yet been sequenced and a synthetic pentapeptide. Current information is given on the in vitro actions of these molecules together with their activity in vivo in animal models. Possibilities for their clinical use are discussed.

Enhanced granulocyte function in a case of chronic granulocytic leukemia in a dog

Chronic granulocytic leukemia is a rare myeloproliferative disorder in dogs. The present study investigated various functions of leukemic granulocytes in a dog that presented with thrombocytopenic purpura, anaemia and a classical leukemic hemogram. All analyses were performed in parallel with a control dog. Purification of the leukemic granulocytes by density gradient centrifugation revealed three neutrophil and neutrophil precursor populations with different densities. Comparison of cell morphology and density showed that cell density increasid with increasing maturity. The control dog possessed only one neutrophil population, with a density greater than 1.077. Analysis of cellular contents of the granular enzymes, elastase, myeloperoxidase and lysozyme showed that leukemic neutrophils were quantitatively markedly different from normal neutrophils with respect to enzyme activities. There were no major differences between leukemic and normal cells as regards aggregatory and migratory responses to different stimuli. The phagocytic capacity of the leukemic cells, however, was dramatically increased compared with the control, and exceeded all previously encountered responses in the assay employed. In a similar fashion, superoxide generation and secretion of elastase and lysozyme in response to zymosan and phorbol myristate acetate were substantially higher than in the control dog. Priming of cell function to a level exceeding that normally attainable in neutrophils appears to have taken place in peripheral blood of the leukemic dog. The only endogenous mediator known to prime neutrophil functions to extent seen in the present case is the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which is intimately involved in regulation of myelopoiesis in mammals. On the basis of the enzymological and functional findings in the leukemic dog, we hypothesize that a lactoferrin deficiency in leukemic neutrophils leads to enhanced GM-CSF synthesis, which is ultimately the cause of the observed cellular hyperresponsiveness and contributes to the monocytosis seen in the patient.

Down Regulation of Myelopoiesis by Mediators Inhibiting the Production of Macrophage-Derived Granulomonopoietic Enhancing Activity (GM-EA)

Monocyte-derived lipid-containing macrophages (MDLMs) constitutively synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates the function of granulocyte-macrophage colony-stimulating activity (GM-CSA). In the study reported, we show that GM-EA is distinct from interleukin-1 (IL-1) in biochemical and functional properties and that its production is negatively regulated by several mediators. Thus, MDLM cultures pretreated with interferon-gamma (IFN-gamma, 3 to 900 U/mL), prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF, 10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated controls. The relative potency of inhibition was in the order of IFN-gamma greater than or equal to PGE2 greater than LF. The extent of the inhibitory effects was proportional to dosage and the duration of treatment and could be observed following only a brief exposure (two hours) of the MDLMS to physiologic doses of the mediators. Under optimal conditions, IFN-gamma (300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours) could totally abrogate the ability of the MDLMs to produce GM-EA. However, the drug-inhibited MDLMs could be reactivated to produce GM-EA by treatment with zymosan (60 micrograms/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-gamma, PGE2, and LF may involve the inhibition of GM-EA production. Furthermore, this negative feedback control is reversible and can be overridden when a proper stimulatory signal is given.

Down regulation of myelopoiesis by mediators inhibiting the production of macrophage-derived granulomonopoietic enhancing activity (GM-EA)

Monocyte-derived lipid-containing macrophages (MDLMs) constitutively synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates the function of granulocyte-macrophage colony-stimulating activity (GM-CSA). In the study reported, we show that GM-EA is distinct from interleukin-1 (IL-1) in biochemical and functional properties and that its production is negatively regulated by several mediators. Thus, MDLM cultures pretreated with interferon-gamma (IFN- gamma, 3 to 900 U/mL), prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF, 10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated controls. The relative potency of inhibition was in the order of IFN-gamma greater than or equal to PGE2 greater than LF. The extent of the inhibitory effects was proportional to dosage and the duration of treatment and could be observed following only a brief exposure (two hours) of the MDLMS to physiologic doses of the mediators. Under optimal conditions, IFN-gamma (300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours) could totally abrogate the ability of the MDLMs to produce GM-EA. However, the drug- inhibited MDLMs could be reactivated to produce GM-EA by treatment with zymosan (60 micrograms/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-gamma, PGE2, and LF may involve the inhibition of GM-EA production. Furthermore, this negative feedback control is reversible and can be overridden when a proper stimulatory signal is given.

The production of myeloid blood cells and their regulation during health and disease

The regulation of myelopoiesis in vivo most likely entails a complex set of interactions between cell-derived biomolecules and their target cells: hematopoietic stem and progenitor cells and accessory cells. Stimulating and suppressing factors have been characterized through in vitro studies, and their mechanisms of action in vitro and in vivo have begun to be elucidated. Among those factors being studied are the hematopoietic colony-stimulating factors (CSF): interleukin-3 (multi-CSF), granulocyte-macrophage-CSF, granulocyte-CSF, and macrophage-CSF; other molecules include erythropoietin, B-cell-stimulating factor-1, interleukin-1, interleukin-2, prostaglandin E, leukotrienes, acidic ferritins, lactoferrin, transferrin, the interferons-gamma, -alpha, and -beta, and the tumor necrosis factors-alpha and -beta (lymphotoxin). These factors interact to modulate blood cell production in vitro and in vivo. The proposed review characterizes these biomolecules biochemically and functionally, including receptor-ligand interactions and the secondary messengers within the cell which mediate their functional activity. The production and action of the molecules are described under conditions of hematopoietic disorders, as well as under normal conditions. Studies in vitro are correlated with studies in vivo using animal models to give an overall view of what is known about these molecules and their relevance physiologically and pathologically.

Regulation of myelopoiesis

Myeloid cells are produced by the bone marrow from stem cells and progenitor cells. This review summarizes the current understanding of how this process is regulated. Regulation of progenitor cell proliferation and differentiation occurs in microenvironments present within the bone marrow as well as on the systemic level by the release of regulators into the circulation. The regulators of central importance to myelopoiesis are growth factors necessary for the proliferation and differentiation of progenitors. These growth factors have recently been characterized and studies indicate that there is a hierarchy of factors acting upon successive differentiation stages of progenitors. Endotoxin appears to be a major modulator of myeloid growth factor production. Other inhibitors of myelopoiesis are also discussed. Regulation of myelopoiesis therefore involves a balance between growth factor production and inhibition by other factors.