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At least 649 records · Page 36Linked to original sources
PubMed2002

The p53 tumour suppressor inhibits glucocorticoid-induced proliferation of erythroid progenitors.

Hypoxia encountered at high altitude, blood loss and erythroleukemia instigate stress erythropoiesis, which involves glucocorticoid-induced proliferation of erythroid progenitors (ebls). The tumour suppressor p53 stimulates hematopoietic cell maturation and antagonizes glucocorticoid receptor (GR) activity in hypoxia, suggesting that it may inhibit stress erythropoiesis. We report that mouse fetal liver ebls that lack p53 proliferate better than wild-type cells in the presence of the GR agonist dexamethasone. An important mediator of GR-induced ebl self-renewal, the c-myb gene, is induced to higher levels in p53(-/-) ebls by dexamethasone. The stress response to anemia is faster in the spleens of p53(-/-) mice, as shown by the higher levels of colony forming units erythroids and the increase in the CD34/c-kit double positive population. Our results show that p53 antagonizes GR-mediated ebl expansion and demonstrate for the first time that p53-GR cross-talk is important in a physiological process in vivo: stress erythropoiesis.

Animals↗
PubMed1998

Stochastic, stage-specific mechanisms account for the variegation of a human globin transgene.

The random insertion of transgenes into the genomic DNA of mice usually leads to widely variable levels of expression in individual founder lines. To study the mechanisms that cause variegation, we designed a transgene that we expected to variegate, which consisted of a beta-globin locus control region 5' HS-2 linked in tandem to a tagged human beta-globin gene (into which a Lac-Z cassette had been inserted). All tested founder lines exhibited red blood cell-specific expression, but levels of expression varied >1000-fold from the lowest to the highest expressing line. Most of the variation in levels of expression appeared to reflect differences in the percentage of cells in the peripheral blood that expressed the transgene, which ranged from 0.3% in the lowest expressing line to 88% in the highest; the level of transgene expression per cell varied no more than 10-fold from the lowest to the highest expressing line. These differences in expression levels could not be explained by the location of transgene integration, by an effect of beta-galactosidase on red blood cell survival, by the half life of the beta-galactosidase enzyme or by the age of the animals. The progeny of all early erythroid progenitors (BFU-E colony-forming cells) exhibited the same propensity to variegate in methylcellulose-based cultures, suggesting that the decision to variegate occurs after the BFU-E stage of erythroid differentiation. Collectively, these data suggest that variegation in levels of transgene expression are due to local, integration site-dependent phenomena that alter the probability that a transgene will be expressed in an appropriate cell; however, these local effects have a minimal impact on the transgene's activity in the cells that initiate transcription.

Age Factors↗
PubMed1998

Human parathyroid hormone does not influence human erythropoiesis in vitro.

BACKGROUND: Although renal anaemia is associated with secondary hyperparathyroidism, the relationship of both conditions remains obscure. Previously it was reported that high levels of bovine parathyroid hormone (PTH) did not inhibit in vitro human erythropoiesis, but whether human PTH inhibits in vitro human erythropoiesis has not been determined. METHOD: To clarify the direct effects of human biologically active N-terminal (1-34) PTH and intact (1-84) PTH on human haematopoietic progenitor growth, we investigated colony assays of human erythropoiesis and granulomonopoiesis. RESULTS: Neither N-terminal PTH (300 ng/ml) nor intact PTH (5000 pg/ml) inhibited haematopoietic progenitor growth. CONCLUSION: Our findings confirm that human PTH does not directly inhibit human erythropoiesis.

Animals↗
PubMed2005

Effect of L-carnitine on erythroid colony formation in mouse bone marrow cells.

BACKGROUND: l-Carnitine can alleviate uraemic anaemia in haemodialysis patients by improving erythrocyte membrane functions or erythropoiesis, which are depressed under uraemic conditions. l-Carnitine and palmitoyl-l-carnitine were reported to increase the formation of colony-forming unit-erythroid (CFU-E) colonies in cultures of fetal mouse liver cells, an effect that depended on the concentration of palmitoyl-l-carnitine but not of l-carnitine. In this study, we investigated l-carnitine's effect on CFU-E colony formation in cell cultures of mouse bone marrow cells. METHODS: Bone marrow from normal female mice was placed in 35 mm culture dishes containing a medium composed of methylcellulose and various nutrients. The dishes were incubated for 48 h, and the colonies of erythroblasts, which were differentiated from CFU-E, consisting of >/=8 cells, were counted in each dish using an inverted microscope. RESULTS: The numbers of CFU-E colonies correlated well with both the initial numbers of bone marrow cells and concentrations of recombinant human erythropoietin (rhEPO) in the methylcellulose medium. In the presence of 0.5 or 1.0 IU/ml of rhEPO, l-carnitine at concentrations of 200 and 400 micromol/l significantly enhanced CFU-E colony formation (P<0.001). CONCLUSION: l-Carnitine significantly increased the number of CFU-E colonies in mouse bone marrow cell cultures. This finding suggests that l-carnitine stimulates erythropoiesis, partially accounting for its mitigating effect on renal anaemia.

Animals↗
PubMed1995

A role for the distal CCAAT box of the gamma-globin gene in Hb switching.

Hereditary persistence of fetal hemoglobin (HPFH) is a condition manifested by continued expression of the gamma-globin gene in adult life. The four types of HPFH mutations (-117 G-A, -114 C-T, -114 C-G, and 13 bp del) clustered in the vicinity of the distal CCAAT box of the gamma-globin gene suggest the relevance of this region to the fetal-to-adult hemoglobin switching. Functional analysis in erythroid cell lines showed that these HPFH mutations reduced the activity of the gamma-globin promoter in K562 expressing embryonic and fetal globin chains, but not in KU812 expressing fetal and adult globin chains. These results suggest that the distal CCAAT box region has different functions in the fetus and the adult. In vitro, binding of NFE3 to the distal CCAAT box was commonly reduced by these HPFH mutations, suggesting that the binding of NFE3 to the distal CCAAT box may repress the gamma-globin gene in adults. Overlap of the binding sites of NFE3 and CP1, a potential activator, indicates the regulation of the gamma-globin gene by the competition between these factors. In addition, an unknown factor interacting with the -114 C-T HPFH mutant CCAAT box may be involved in elevation of the gamma-globin expression in an individual with the -114 C-T mutation.

Base Sequence↗
PubMed1990

Induction of fetal hemoglobin by cell-cycle-specific drugs and recombinant erythropoietin.

During the last several years, studies in humans and experimental animals have identified several compounds that induce fetal hemoglobin in the adult. These include: cell-cycle-specific drugs, other cytotoxic drugs, butyric acid analogs, and erythropoietin. Several of these compounds induce fetal hemoglobin indirectly by triggering kinetics of rapid erythroid regeneration. High doses of erythropoietin increase the frequency of erythroid progenitors programmed to hemoglobin F. This results in transient increases of hemoglobin F-containing cells (F cells) in the peripheral blood. Erythropoietin and hydroxyurea increase F cells in a cooperative fashion. Although high doses of erythropoietin can induce F cell production in humans, the practical relevance of such observations is unclear

Anemia, Sickle Cell↗
PubMed1999

Apoptosis and polycythemia vera.

Polycythemia vera is an acquired clonal myeloproliferative disorder characterized by increased numbers of erythroid cells, often with a concomitant rise in neutrophils and/or megakaryocytes. Normally, erythropoietin is essential for the survival and proliferation of erythroid progenitors; however in polycythemia vera the erythroid progenitor cells can survive and develop in the absence of erythropoietin. Members of the Bcl-2 family of apoptosis regulators have been shown to mediate the erythropoietin-dependent survival of erythroid cells. In this article, recent advances in understanding the mechanisms used by erythroid progenitors from patients with polycythemia vera to control apoptosis, are discussed.

Animals↗
PubMed1997

Anemia and perinatal death result from loss of the murine ecotropic retrovirus receptor mCAT-1.

The mCAT-1 gene encodes a basic amino acid transporter that also acts as the receptor for murine ecotropic leukemia viruses. Targeted mutagenesis in embryonic stem cells has been used to introduce a germ-line null mutation into this gene. This mutation removes a domain critical for virus binding and inactivates amino acid transport activity. Homozygous mutant pups generated from these cells were approximately 25% smaller than normal littermates, very anemic, and died on the day of birth. Peripheral blood from homozygotes contained 50% fewer red blood cells, reduced hemoglobin levels, and showed a pronounced normoblastosis. Histological analyses of bone marrow, spleen, and liver showed a decrease in both erythroid progenitors and mature red blood cells. Mutant fetal liver cells behaved normally in in vitro hematopoietic colony-forming assays but generated an anemia when transplanted into irradiated C.B.-17 SCID mice. Furthermore, reconstitution of the white cell compartment of SCID mice by mutant fetal liver cells was less complete than that observed with a mixed population of wild-type and heterozygous fetal liver cells. Primary embryo fibroblasts from mutant mice were completely resistant to ecotropic retrovirus infection. Thus, mCAT-1 not only appears to be the sole receptor for a group of murine ecotropic retroviruses associated with hematological disease but also plays a critical role in both hematopoiesis and growth control during mouse development.

Anemia↗
PubMed1992

Responsiveness of bone marrow erythroid progenitors (CFU-E and BFU-E) to recombinant human erythropoietin (rh-Ep) in vitro in multiple myeloma.

The responsiveness of bone marrow erythroid progenitors (CFU-E and BFU-E) to recombinant human erythropoietin (rh-Ep) was investigated in vitro in 21 patients with multiple myeloma to assess the clinical usefulness of rh-Ep in this disease. CFU-E and BFU-E assays were performed by methylcellulose culture methods. The myeloma patients were divided into two groups according to the percentage of plasma cells in the bone marrow (over 50% and under 50%). Among the patients with few plasma cells, some revealed normal CFU-E and BFU-E growth at 2 units of rh-Ep, and no further increase was observed even with an increasing dose of rh-Ep. Among the other patients, more than half demonstrated a good response to rh-Ep. Among the patients with a high percentage of plasma cells, some revealed no response to rh-Ep, but there were patients with a high percentage of plasma cells in the bone marrow who had a good response to rh-Ep. High doses of rh-Ep may be clinically effective in some patients with multiple myeloma independently of the level of plasma cells in the bone marrow.

Aged↗
PubMed1992

The production of steel factor mRNA in Diamond-Blackfan anaemia long-term cultures and interactions of steel factor with erythropoietin and interleukin-3.

Diamond-Blackfan anaemia (DBA) is a congenital macrocytic anaemia. To investigate whether DBA is due to hyporesponsiveness to or hypoproduction of Steel factor (SF), we compared the in vitro responsiveness of the BFU-E contained in the Ficoll-Hypaque non-adherent cell fraction of six DBA marrows with that of four normal marrows and one transient erythroblastopenia of childhood (TEC) marrow. In addition, we studied the effect of soluble SF on long-term marrow cultures (LTMC) and analysed the stromal cells from these cultures for SF mRNA transcripts. All the patients showed an erythropoietin dose-related increase of small BFU-E. The number and size of BFU-E was increased with the addition to the epo of IL-3 or SF; IL-3+SF was not synergistic. The addition of soluble SF to LTMC of DBA patients was associated with a small but consistent increase in non-adherent cell production and an increase in the number of progenitors. Messenger RNA from immortalized stromal cell lines of three patients and from primary bone marrow stromal cells of one patient showed the presence of expected SF transcripts by PCR analysis. These results demonstrate that this group of DBA patients responds to SF and produces SF mRNA normally, indicating that SF itself is not involved in DBA pathophysiology. The effects observed suggest that, despite the lack of evidence for a causative role, SF may prove to be effective treatment for such patients.

Adult↗
PubMed1993

Proliferating normal bone marrow cells do stain for Ki-67 antigen.

The normal human bone marrow has been investigated in the past for the presence of the proliferation associated antigen detected by the Ki-67 antibody and aberrantly low scores for this antigen have been reported. We used a new Ki-67 equivalent antibody (MIB 1) and a formalin fixation of smears and trephine biopsies, and we report 52.8% +/- 9.2 SD of the normal BM cells to stain for MIB 1. Late forms of the maturing blood cells compartment such as metamyelocytes and megakaryocytes were stained in cytokine-treated marrows.

Bone Marrow↗
PubMed1994

Polycythaemia vera. IV. Specific binding of stem cell factor to normal and polycythaemia vera highly purified erythroid progenitor cells.

Polycythaemia vera (PV) patients' blood burst-forming units-erythroid (BFU-E) have an enhanced sensitivity to stem cell factor (SCF) compared to normal BFU-E. To characterize SCF receptors on erythroid progenitors from normal individuals and PV patients, we performed binding experiments using radioiodinated recombinant SCF (rSCF), day 1 BFU-E and day 8 erythroid colony-forming cells (ECFC), which are mostly colony-forming units-erythroid (CFU-E). 125I-rSCF binds to a single class of cell surface receptors (23,000/ECFC) at 0 degrees C with a high-binding affinity (Kd = 17 pM). Saturation occurred at 0.5 nM (10 ng/ml) which produces a nearly maximum biological effect. One half of the radiolabelled rSCF was internalized by the cells after 30 min at 37 degrees C. No significant differences in the receptor number, dissociation constant, or internalization rate were found between normal and PV ECFC. Autoradiographic analysis of 125I-rSCF binding to normal BFU-E and ECFC showed that no differences were present in either the percentage of positive cells or the number of radioactive grains/cell between the normal and PV erythroid progenitors. The enhanced sensitivity of PV BFU-E and CFU-E to SCF does not appear to be related to changes in SCF receptor number, binding affinity or internalization and the hypersensitivity of PV erythroid progenitors to SCF must reside in a further internal cellular abnormality.

Autoradiography↗
PubMed1994

Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo.

Butyrate and other short-chain fatty acids stimulate fetal globin gene expression and have potential for ameliorating the beta globin disorders. Butyrate, however, is rapidly metabolized in vivo and reaches only micromolar concentrations in plasma. We report here that a branched-chain derivative of butyrate, isobutyramide, increases gamma globin gene expression in cultured human erythroid progenitors in vitro and stimulates activity from a minimal gamma globin gene promoter linked to a reporter gene in stable and transient expression assays, with slightly less activity in these in vitro assays than butyrate. In vivo, administration of isobutyramide to anaemic adult baboons rapidly stimulates fetal globin synthesis and F-reticulocyte production. Plasma concentrations at millimolar levels are achieved after a single intravenous or oral dose (500-600 mg/kg), and these concentrations are maintained for 9.5-10.5 h. These results indicate that although isobutyramide has slightly less activity than butyrate in vitro in enhancing fetal globin expression at the cellular and molecular level, its prolonged in vivo half-life may provide superior activity as a therapeutic agent for reactivating fetal globin gene expression in vivo.

Administration, Oral↗
PubMed1994

Acquired sideroblastic anaemia following progesterone therapy.

We report a case of acquired sideroblastic anaemia precipitated by progesterone. On two separate occasions, over 15 years apart, the patient developed sideroblastic anaemia with iron overload shortly after the administration of progesterone. No other cause for sideroblastic anaemia was found, and treatment with folic acid, pyridoxine or androgens corrected the anaemia. In both instances removal of the progestational agent led to prompt disappearance of the anaemia as well as the ringed sideroblasts. Using a two-phase liquid culture procedure in which human peripheral blood-derived progenitor cells undergo erythroid proliferation and differentiation, we demonstrated enhanced sensitivity of the patient's erythroid progenitors to progesterone. We conclude that progesterone should be added to the list of medications known to be associated with acquired sideroblastic anaemia.

Adult↗
PubMed1995

The determination of spontaneous megakaryocyte colony formation is an unequivocal test for discrimination between essential thrombocythaemia and reactive thrombocytosis.

Spontaneous colony formation from bone marrow megakaryocyte progenitors (BMsCFU-Mk) was studied in 24 patients with essential thrombocythaemia (ET), 20 patients with reactive thrombocytosis (RT), 20 patients with polycthaemia rubra vera with thrombocytosis (PRVtr), 16 patients with chronic myeloid leukaemia with thrombocytosis (CMLtr) and 18 normal control subjects (C). The culture medium which was used in the methylcellulose assay in vitro contained 30% of plasma from a single patient with hereditary haemochromatosis. Remarkable BMsCFU-Mk growth was recorded in all patients with ET but in none with RT or in C. BMs-CFU-Mk were present in 11/20 patients with PRVtr and 7/16 patients with CMLtr. Spontaneous bone marrow erythroid progenitors (BMsBFU-E) were also determined in these patients. BMsBFU-E were found in 21/24 patients with ET and none in the patients with RT and C. All patients with PRVtr and one patient with CMLtr showed BMsBFU-E. We conclude that our implementation of the in vitro methylcellulose assay allows the BMsCFU-Mk to be used as an unequivocal test for discrimination between ET and RT which has not been shown in previously published studies. In addition, we present evidence that in 10 patients BMsCFU-Mk and/or BMsBFU-E growth in the test persisted after long-lasting haematological remission.

Adult↗
PubMed1993

Suppression of erythroid progenitor cells during malarial infection in Thai adults caused by serum inhibitor.

The bone marrows of 21 Thai adults infected with Plasmodium falciparum malaria were cultured for CFU-E and BFU-E by using AB serum, autologous serum (parasitaemia) and autologous serum (post-parasitaemia). Six patients had no complication and 15 patients had pulmonary, renal or haematologic complications. In the non-complicated cases, sera during parasitaemia did not suppress the post-parasitaemia CFU-E and BFU-E. Post parasitaemia, there was suppression of CFU-E by parasitaemia sera. In the complicated cases, the autologous sera during parasitaemia suppressed the growth of both CFU-E and BFU-E both during and after parasitaemia (P < 0.05). The post-parasitaemia sera had neither a suppressive nor a stimulating effect. In the complicated cases, the progenitor cells cultured from the bone marrow post-parasitaemia were fewer in number than those cultured from the bone marrow during parasitaemia using the same sera. Two possible mechanisms of suppression are postulated, namely the reduction of erythropoietin or the increased tumour necrosis factor during malarial infection. Further studies to clarify this are being carried out.

Adult↗
PubMed2004

Differentiation status dependent function of FOG-1.

The molecular interactions between transcription factors and cofactors play crucial roles in various biological processes, including haematopoiesis. FOG-1 is a cognate cofactor of GATA-1, and the FOG-1/GATA-1 complex is essential for the haematopoietic differentiation of erythroid cells and megakaryocytes. In order to elucidate the biological functions of FOG-1 in the different contexts of cell differentiation, we analysed the effects of FOG-1 expression on haematopoietic cell differentiation, using a combination of in vitro differentiation of mouse embryonic stem (ES) cells and conditional gene expression. FOG-1 suppressed the proliferation of primitive and definitive erythroid cells in all stages of differentiation. However, FOG-1 inhibited and enhanced megakaryopoiesis in the early and late differentiation stages, respectively, through different molecular mechanisms. In addition, FOG-1 inhibited the proliferation of ES cells, the molecular mechanism of which differs from those of erythroid and megakaryocytic cells. These results suggest that FOG-1 functions in a cell differentiation context-dependent manner.

Animals↗