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PubMed1980

2,3-Bisphosphoglycerate in developing rabbit erythroid cells.

Rabbits were made anemic to different extents by phenylhydrazine injections so as to vary the developmental stages of the erythroid cells in their peripheral blood and bone marrow. It was found that the more severe the anemia, the lower the concentration of glycerate-2,3-P2 in the bone marrow cells and in the circulating erythroid cells. The glycerate-2,3-P2 level was shown to rise during erythroid differentiation in a linear relationship to the hemoglobin level, corresponding to the equation Y = 0.03x + 0.29, where y is the concentration of glycerate-2,3-P2 (micromoles per ml packed cells) and x is the concentration of hemoglobin (milligrams per packed cells). The bone marrow cells were fractionated on a size (i.e. maturity) basis and enzyme activities in the fractionated cells were measured. The accumulation of glycerate-2,3-P2 was found to be primarily attributable to the increase in glycerate-2,3-P2 synthase activity. Glycerate-2,3-P2 phosphatase and phosphofructokinase increased as the cells matured from the polychromatic stages to become reticulocytes while pyruvate kinase and phosphoglyceromutase decreased. The changes in phosphofructokinase and pyruvate kinase appear to be advantageous for glycerate-2,3-P2 accumulation. The two enzyme activities directly responsible for the synthesis and the breakdown of glycerate-2,3-P2 are probably manifested by a single protein, glycerate-2,3-P2 synthase-phosphatase.

Anemia↗
PubMed2001

Biological significance of MAPK, AKT and JAK-STAT protein activation by various erythropoietic factors in normal human early erythroid cells.

The aim of this study was to identify signal transduction pathways activated by erythropoietin (EpO) and erythropoietin co-stimulatory factors (kit ligand), insulin-like growth factor, thrombopoietin, interleukin 3 and granulocyte-macrophage colony-stimulating factor) in normal human bone marrow CD34(+) cells and d 11 erythroid burst forming unit derived glycophorin+ cells. The activation of these signal transduction pathways was further correlated with various biological effects such as (i) cell proliferation, (ii) inhibition of apoptosis, (iii) activation of adhesion and (iv) secretion of the matrix metalloproteinases (MMPs) MMP-9 and MMP-2, and vascular endothelial growth factor (VEGF). We found that in human CD34(+) cells and erythroblasts erythropoietic factors may activate similar but different signalling pathways, and that activation of each of the JAK-STAT, MAPK p42/44 or PI-3K-AKT axes alone is not sufficient either to stimulate cell proliferation or inhibit apoptosis, suggesting that these processes are regulated by orchestrated activation of multiple signalling cascades. Accordingly, we found that although cell proliferation was more related to simultaneous activation of JAK-STAT and MAPK p42/44, the effect on cell survival correlated with activation of PI-3K-AKT, MAPK p42/44 and JAK-STAT proteins. We also demonstrated that differentiating normal human erythroid cells lose their adhesive properties and secrete angiopoietic factors such as MMP-9, MMP-2 and VEGF, and we postulate that this secretion by early erythroid cells may play a role in their maturation and egress from the haematopoietic niches of the bone marrow.

Antigens, CD34↗
PubMed2002

The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells.

The t(8;21) translocation, which encodes the AML1-ETO fusion protein (now known as RUNX1-CBF2T1), is one of the most frequent translocations in acute myeloid leukemia, although its role in leukemogenesis is unclear. Here, we report that exogenous expression of AML1-ETO in human CD34(+) cells severely disrupts normal erythropoiesis, resulting in virtual abrogation of erythroid colony formation. In contrast, in bulk liquid culture of purified erythroid cells, we found that while AML1-ETO initially inhibited proliferation during early (erythropoietin [EPO]-independent) erythropoiesis, growth inhibition gave way to a sustained EPO-independent expansion of early erythroid cells that continued for more than 60 days, whereas control cultures became growth arrested after 10 to 13 days (at the EPO-dependent stage of development). Phenotypic analysis showed that although these cells were CD13(-) and CD34(-), unlike control cultures, these cells failed to up-regulate CD36 or to down-regulate CD33, suggesting that expression of AML1-ETO suppressed the differentiation of these cells and allowed extensive self-renewal to occur. In the early stages of this expansion, addition of EPO was able to promote both phenotypic (CD36(+), CD33(-), glycophorin A(+)) and morphologic differentiation of these cells, almost as effectively as in control cultures. However, with extended culture, cells expressing AML1-ETO became refractory to addition of this cytokine, suggesting that a block in differentiation had been established. These data demonstrate the capacity of AML1-ETO to promote the self-renewal of human hematopoietic cells and therefore support a causal role for t(8;21) translocations in leukemogenesis.

Antigens, CD34↗
PubMed1995

Regulated production of a pleiotropic cytokine-platelet-derived growth factor--by differentiating erythroid cells in vitro and in vivo.

Erythroid progenitor growth in vitro is stimulated by exogenous platelet-derived growth factor (PDGF). We now report that both normal and transformed erythroid progenitor cells produce authentic PDGF in vitro and in vivo. Importantly, this production is highly regulated during erythropoiesis. Addition of soluble lysates from Rauscher murine erythroleukemia cells--an erythropoietin-responsive model progenitor cell line--to quiescent BALB/c 3T3 fibroblasts resulted in a mitogenic response identical to that observed with the addition of authentic recombinant PDGF. Polyclonal and monoclonal anti-PDGF antibodies immunoabsorbed 50-100% of this activity. Induction of Rauscher cell differentiation in vitro with dimethyl sulfoxide or erythropoietin for 48-72 hr markedly upregulated PDGF production by 17- to 18-fold and 14- to 38-fold, respectively. Importantly, stimulation of normal erythropoiesis in vivo in mice treated either with phenylhydrazine or with erythropoietin increased PDGF levels in the spleen by 11- to 48-fold and 20- to 34-fold, respectively. These results strongly suggest a role for erythroid cell-derived PDGF in normal erythropoiesis and provide documentation of the regulated production of a pleiotropic cytokine by erythroid cells.

3T3 Cells↗
PubMed1988

Protooncogene expression in normal, preleukemic, and leukemic murine erythroid cells and its relationship to differentiation and proliferation.

The expression of 18 protooncogenes was examined by Northern blot analysis in preleukemic and leukemic stages of murine erythroleukemias induced by Friend viruses. As controls, erythropoietically stimulated spleens from phenylhydrazine-treated mice were studied. Expression of 10 protooncogenes (c-erb-A, c-erb-B, c-ets, c-sis, c-mos, c-rel, c-src, c-fes, c-fms, N-myc [corrected] was not detectable in Friend erythroleukemias. One protooncogene (c-src) was found expressed in normal erythroid cells but not in erythroleukemias. Four protooncogenes (c-fos, c-abl, N-ras, and c-raf) were expressed at low levels in both steps of erythroleukemia. c-fos and c-abl RNAs were barely detectable in normal erythroid cells. High levels of four protooncogene transcripts (c-H-ras, c-K-ras, c-myc, and c-myb) were detected in preleukemic and leukemic tissues. While c-H-ras RNA was found at similar levels in normal and leukemic erythroid cells, c-myc, c-myb, and c-K-ras were not expressed in normal erythroid cells. To determine whether the elevated levels of c-myc, c-myb, and c-K-ras RNAs in erythroleukemic cells are related to the proliferative state or the undifferentiated state of the cells, the effect of dimethyl sulfoxide-induced differentiation on oncogene expression in two erythroleukemia cell lines was examined. Terminal differentiation was associated with lack of c-myb expression while c-myc and c-K-ras expression was essentially unaffected. These results suggest that the high levels of c-myb transcripts in erythroleukemias may reflect the undifferentiated state of the leukemic cells. In contrast, the elevated expression of c-myc and c-K-ras at both stages of the Friend diseases is probably not related to the stage of differentiation but rather to the uncontrolled proliferation of the cells. Finally among 18 protooncogenes surveyed, only the accumulation of c-myc and c-K-ras RNAs appears to be associated with the Friend erythroleukemic process before the late leukemic phase develops.

Animals↗
PubMed1998

AP1 regulation of proliferation and initiation of apoptosis in erythropoietin-dependent erythroid cells.

The transcription factor AP1 has been implicated in the induction of apoptosis in cells in response to stress factors and growth factor withdrawal. We report here that AP1 is necessary for the induction of apoptosis following hormone withdrawal in the erythropoietin (EPO)-dependent erythroid cell line HCD57. AP1 DNA binding activity increased upon withdrawal of HCD57 cells from EPO. A dominant negative AP1 mutant rendered these cells resistant to apoptosis induced by EPO withdrawal and blocked the downregulation of Bcl-XL. JunB is a major binding protein in the AP1 complex observed upon EPO withdrawal; JunB but not c-Jun was present in the AP1 complex 3 h after EPO withdrawal in HCD57 cells, with a concurrent increase in junB message and protein. Furthermore, analysis of AP1 DNA binding activity in an apoptosis-resistant subclone of HCD57 revealed a lack of induction in AP1 DNA binding activity and no change in junB mRNA levels upon EPO withdrawal. In addition, we determined that c-Jun and AP1 activities correlated with EPO-induced proliferation and/or protection from apoptosis. AP1 DNA binding activity increased over the first 3 h following EPO stimulation of HCD57 cells, and suppression of AP1 activity partially inhibited EPO-induced proliferation. c-Jun but not JunB was present in the AP1 complex 3 h after EPO addition. These results implicate AP1 in the regulation of proliferation and survival of erythroid cells and suggest that different AP1 factors may play distinct roles in both triggering apoptosis (JunB) and protecting erythroid cells from apoptosis (c-Jun).

Apoptosis↗
PubMed1983

Kinetics of dexamethasone binding to the glucocorticoid receptor of intact erythroid cells from rat fetal liver.

The erythroid cells from the rat fetal liver have been shown to possess a receptor for glucocorticoids. In the present work, the characteristics of [3H]dexamethasone binding have been studied on intact cells, in order to minimize receptor degradation, and at 4 degrees C, in order to prevent the activation of the hormone-receptor complex. Dissociation kinetics were those of a first-order reaction and the value of the rate constant of dissociation was similar to the values available in the literature. When studied at low concentrations of the ligand and using short-term incubations, association kinetics were apparently those of a simple bimolecular reaction. But at high ligand concentrations and/or using long-term incubations, association kinetics indicated a more complex reaction. Our results were compatible with the model proposed by Pratt W.B., Kaine J.L. and Pratt V.D. (J. Biol. Chem. 250 (1975) 4584-4591) for cytosolic preparations. This model implies the rapid formation of a transient unstable form of the complex, further converted into a stable form with slower kinetics. Equilibrium dissociation constant of the first (rapid) reaction was 80 microM and the rate constant of 'stabilization' was of the order of 70 X 10(-3) min-1. These values agree with the results of Pratt et al. relative to a cytosolic preparation from rat thymocytes.

Animals↗
PubMed1984

Two populations of erythroid cell progenitors in paroxysmal nocturnal hemoglobinuria.

We have grown erythroid cell colonies from two patients with paroxysmal nocturnal hemoglobinuria (PNH). At 11 to 13 days, individual bursts were picked and incubated for 24 hours with 3H-leucine in order to label total cell protein (mainly hemoglobin). After appropriate washing, each burst was subjected to a miniaturized acidified serum test, and lysis was measured by the release of radioactivity. In bursts from normal controls, lysis was 19% +/- 13% SD. By contrast, of 58 bursts from PNH patients, 14 had lysis similar to that of controls (mean 15.4% +/- 10.6%), while 44 had lysis ranging from 42.2% to 85.8% (mean 70.3% +/- 10.4%). Colonies sensitive to acidified serum were acetylcholinesterase (AchE) negative, whereas normal colonies were AchE-positive. Thus, based on two independent criteria, a dual population of erythroid burst-forming units (BFU-E) can be demonstrated in PNH. These data confirm directly the somatic mutation model of the pathogenesis of PNH, and by these methods the relative sizes of the normal and the PNH cell populations can be measured at the level of the erythroid cell precursors.

Acetylcholinesterase↗
PubMed1979

Production and fate of erythroid cells in anaemic Xenopus laevis.

Adult Xenopus laevis, rendered anaemic by phenylhydrazine injection, have been studied during the recovery from such anaemia. Electron microscopy of liver and spleen sections indicates that both of these organs are active in the phagocytosis and destruction of the old damaged red blood cells. May-Grunwald and Giemsa staining of liver and spleen cells following anaemia has been used to show that erythropoiesis also occurs in both liver and spleen, and this has been confirmed by electron-microscope studies of these organs. Cell counting and radiolabelling of the new population of circulating erythroid cells in the period following phenylhydrazine injection suggests that a sudden release of basophilic erythroblasts from liver and spleen is followed by mitosis of this new cell population in circulation, and that no further release of erythroid cells from these organs is likely until complete recovery has occurred.

Anemia↗
PubMed1985

How do retroviral oncogenes induce transformation in avian erythroid cells?

The v-erb B oncogene, as well as other oncogenes of the src-gene family transform immature erythroid cells from chick bone marrow in vivo and in vitro. The erb B-transformed erythroid cells differ from normal late erythroid precursors (CFU-E) in that they have acquired the capacity to undergo self-renewal as well as to differentiate terminally. They also do not require the normal erythroid differentiation hormone, erythropoietin, for either process. Cooperation of v-erb B with a second oncogene, v-erb A, results in a differentiation arrest of the transformed cells, which now only use the self-renewal pathway. Studies with conditional and non-conditional mutants in both v-erb B and v-erb A will be presented to elucidate further how the transforming proteins encoded by these oncogenes, gp74erb B and gp75gag-erb A, affect the differentiation programme of the infected erythroid precursor with the outcome of hormone-independent leukaemic cells arrested at an early stage of erythroid differentiation.

Animals↗
PubMed1984

src- and fps-containing avian sarcoma viruses transform chicken erythroid cells.

We report here that several oncogene-transducing avian sarcoma virus strains, namely Rous sarcoma virus (src), Fujinami sarcoma virus (fps), and PRCII (fps), transform avian erythroid cells in vitro and in vivo. The src- and fps-transformed erythroblasts grow in vitro for 20-30 generations, require special growth conditions, and tend to differentiate spontaneously. In these properties, they resemble erythroid cells transformed with the erbB-containing H strain of avian erythroblastosis virus (AEV-H) but differ from those transformed with AEV-ES4 (erbA, erbB), which grow under standard culture conditions and rarely differentiate spontaneously. Erythroblasts transformed with viruses carrying temperature-sensitive mutations in the src or fps oncogene and then shifted to the nonpermissive temperature in the presence of anemic serum (as a source of an erythropoietin-like factor) differentiate terminally into erythrocytes. These results demonstrate that several members of the src gene family other than erbB have the capacity to transform erythroid cells.

Animals↗
PubMed1975

Direct effects of thyroid hormones on bone marrow erythroid cells of rats.

A stimulatory effect on bone marrow cellularity was observed in normal and nephrectomized rats continuously infused with T3 and T4. Results of bone marrow studies are expressed in absolute numbers of total nucleated erythroid cells per milligram of femoral marrow at the beginning and after 8 hr of continuous intravenous infusions. Administration of T3 and T4 to nephrectomized rats produced a marked and significant increase in total erythroid cells counted. After differential analyses of the nucleated erythroid elements, a significant increase in all erythroid cell types was also observed. Similar results were seen in a control group of rats in which both ureters have been previously ligated and in groups of nephrectomized rats receiving rabbit antiserum against erythropoietin before starting the intravenous infusions of T3 and T4. These results indicate that stimulation of marrow erythropoiesis produced by thyroid hormones in our system is not dependent on renal or extra-renal production of erythropoietin. The progressive introduction of T3 and T4 into the circulation of rats with bilateral nephrectomy or ureter-ligated normal rats, may overload the mechanism of transport of these hormones in plasma. As a consequence, a progressive increase in free active forms of T3 and T4 in plasma may occur. Our interpretation of the present findings is that thyroid hormones stimulate directly bone marrow erythropoiesis. This stimulation is clearly evident when high levels of free active forms of thyroid hormones are present in plasma.

Animals↗
PubMed2006

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci.

Erythropoiesis is under fine control and genetic loci that affect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis, we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing. Different autosomal loci affect bone marrow (chromosomes 5, 11 and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (Epo) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggest a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.

Animals↗
PubMed1992

Transferrin receptor gene is hyperexpressed and transcriptionally regulated in differentiating erythroid cells.

We have analyzed the developmental pattern of expression of the chicken transferrin receptor (CTR) gene in various chick embryonic tissues. Northern analyses of RNA from embryonic tissues at different stages of development and cultured chick embryonic fibroblasts (CEFs) show that CTR is hyperexpressed in differentiating erythroid cells such that the steady-state level of CTR mRNA in these cells could be 200 or more times higher than in nonerythroid cells. In vitro nuclear transcription assays using nuclei from embryonic erythroid and brain cells, as well as CEFs, demonstrate that the vast differences in CTR mRNA levels in these cells are reflected in their respective CTR gene transcriptional activities. During development, the steady-state level of CTR mRNA declines in all tissues and, in erythroid cells, this pattern is accompanied by a similar decline in beta-globin mRNA levels. These changes are concurrent with the decreases in CTR and beta-globin mRNA transcriptional activities during erythroid maturation. Taken together, our results indicate that the hyperexpression of the CTR gene in differentiating erythroid cells is regulated to a significant degree at the transcriptional level. We also demonstrate that, in erythroid cells, neither CTR gene transcription nor CTR mRNA stability is regulated by intracellular iron levels.

Animals↗
PubMed2004

Neurokinin-B transcription in erythroid cells: direct activation by the hematopoietic transcription factor GATA-1.

The GATA family of transcription factors establishes genetic networks that control developmental processes including hematopoiesis, vasculogenesis, and cardiogenesis. We found that GATA-1 strongly activates transcription of the Tac-2 gene, which encodes proneurokinin-B, a precursor of neurokinin-B (NK-B). Neurokinins function through G protein-coupled transmembrane receptors to mediate diverse physiological responses including pain perception and the control of vascular tone. Whereas an elevated level of NK-B was implicated in pregnancy-associated pre-eclampsia (Page, N. M., Woods, R. J., Gardiner, S. M., Lomthaisong, K., Gladwell, R. T., Butlin, D. J., Manyonda, I. T., and Lowry, P. J. (2000) Nature 405, 797-800), the regulation of NK-B synthesis and function are poorly understood. Tac-2 was expressed in normal murine erythroid cells and was induced upon ex vivo erythropoiesis. An estrogen receptor fusion to GATA-1 (ER-GATA-1) and endogenous GATA-1 both occupied a region of Tac-2 intron-7, which contains two conserved GATA motifs. Genetic complementation analysis in GATA-1-null G1E cells revealed that endogenous GATA-2 occupied the same region of intron-7, and expression of ER-GATA-1 displaced GATA-2 and activated Tac-2 transcription. Erythroid cells did not express neurokinin receptors, whereas aortic and yolk sac endothelial cells differentially expressed neurokinin receptor subtypes. Since NK-B induced cAMP accumulation in yolk sac endothelial cells, these results suggest a new mode of vascular regulation in which GATA-1 controls NK-B synthesis in erythroid cells.

Animals↗
PubMed1986

[Erythroid cells of the bone marrow of the mouse].

The bone marrow of three intact male mice of C57Bl/6 line, fixed by perfusion of isotonic fixative of Karnovsky, has been studied by means of the scanning electron microscopy method. The surface of erythroid cells, that are immediately connected with macrophages of the erythroblasts islets, is analysed. According to the surface form, the erythroid cells are devided into 5 types. Every maturation stage of the erythroid cells is characterized by a certain type of surface. For identification of basophilic and polychromatophilic proerythrocytes the combined method of light and electron scanning microscopy of the cells in suspension is used. The bone marrow cells, obtained from the two male mice of C57Bl/6 line are fixed with the same fixative on special glasses with grids traced on them, stained after Romanovsky-Giemsa method and in moist preparations are examined in the light microscope. After further treatment the surface of the same cells in studied in the scanning electron microscope.

Animals↗
PubMed1991

The erythropoietin receptor gene: cloning and identification of multiple transcripts in an erythroid cell line OCIM1.

The hormone erythropoietin is necessary for the maintenance, generation, and maturation of erythroid cells. This kidney-derived glycoprotein binds to cell-surface receptors, mediating both the proliferation and differentiation of erythroid cells. We have characterized 16 human erythropoietin receptor cDNA clones from two cDNA libraries prepared from OCIM1 poly(A)-containing mRNA. Of these 16 isolates, many showed evidence of incorrect RNA splicing events; others contained small deletions yielding multiple transcripts that may play a role in their erythroleukemic state. The human erythropoietin receptor, as deduced from the sequence of these clones, encodes a 508-amino-acid molecule, including a 24-residue signal peptide, a 226-amino-acid external domain, a transmembrane spanning region of 22 amino acids, and a cytoplasmic domain of 236 amino acids. There is an 80% overall homology between the human and murine erythropoietin receptor sequences.

Amino Acid Sequence↗