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PubMed2006

Broadening of DNA replication origin usage during metazoan cell differentiation.

We have examined whether replication of the chicken beta-globin locus changes during differentiation of primary erythroid progenitors into erythrocytes. In undifferentiated progenitors, four principal initiation sites and a replication fork pausing region (RFP) were observed. Forty-eight hours after induction of differentiation, the principal sites were maintained, even in the activated beta(A)-globin gene, some minor sites were enhanced, three new sites appeared and the RFP disappeared. One of the activated origins showed increased histone H3 K9K14 diacetylation, but the others did not. These results demonstrate a broadening of DNA replication origin usage during differentiation of untransformed metazoan cells and indicate that histone H3 diacetylation, other histone modifications so far reported and transcription are not crucial determinants of origin selection in this system.

Acetylation↗
PubMed2006

Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome.

Erythroid dysplasia is the pathologic hallmark of myelodysplastic syndromes (MDS). To develop a quantitative flow-cytometry approach to its evaluation, we analyzed the expression of CD71, CD105, cytosolic H-ferritin (HF), cytosolic L-ferritin (LF) and mitochondrial ferritin (MtF) in erythroblasts from 104 MDS patients, 69 pathologic control patients and 19 healthy subjects. Six-parameter, 4-color flow cytometry was employed, and data were expressed as mean fluorescence intensity. Compared with pathologic and healthy controls, MDS patients had higher expression of HF (P < 0.001) and CD105 (P < 0.001), and lower expression of CD71 (P < 0.001). MtF was specifically detected in MDS with ringed sideroblasts, and there was a close relationship between its expression and Prussian blue staining (r = 0.89, P < 0.001). In vitro cultures of myelodysplastic hematopoietic progenitors showed that both HF and MtF were expressed at a very early stage of erythroid differentiation, and that MtF expression is specifically related to mitochondrial iron loading. A classification function based on expression levels of HF, CD71 and CD105 allowed us to correctly classify > 95% of MDS patients. This flow-cytometry approach provides an accurate quantitative evaluation of erythroid dysplasia and allows a reliable diagnosis of sideroblastic anemia, and may therefore be a useful tool in the work-up of patients with MDS.

Adult↗
PubMed2003

Mammalian linker-histone subtypes differentially affect gene expression in vivo.

Posttranslational modifications and remodeling of nucleosomes are critical factors in the regulation of transcription. Higher-order folding of chromatin also is likely to contribute to the control of gene expression, but the absence of a detailed description of the structure of the chromatin fiber has impaired progress in this area. Mammalian somatic cells contain a set of H1 linker-histone subtypes, H1 (0) and H1a to H1e, that bind to nucleosome core particles and to the linker DNA between nucleosomes. To determine whether the H1 histone subtypes play differential roles in the regulation of gene expression, we combined mice lacking specific H1 histone subtypes with mice carrying transgenes subject to position effects. Because position effects result from the unique chromatin structure created by the juxtaposition of regulatory elements in the transgene and at the site of integration, transgenes can serve as exquisitely sensitive indicators of chromatin structure. We report that some, but not all, linker histones can attenuate or accentuate position effects. The results suggest that the linker-histone subtypes play differential roles in the control of gene expression and that the sequential arrangement of the linker histones on the chromatin fiber might regulate higher-order chromatin structure and fine-tune expression levels.

Anemia, Hemolytic↗
PubMed1978

Proteolytic activity in erythrocyte precursors.

Thalassemia is characterized by unequal rates of synthesis of the alpha and beta globin chains that are part of the hemoglobin tetramer. In the type of thalassemia due to a defect in beta-chain synthesis (beta-thalassemia), this imbalance results in a relative exoess of alpha-chains. We have studied the susceptibility of excess free alpha-chains to proteolysis. Incubation of isotopically labeled peripheral blood lysates from individuals with beta-thalassemia trait in the presence of bone marrow or normoblast lysates from thalassemic or hematologically normal individuals resulted in a decrease in the alpha/beta ratio and a loss of free alpha-chain radioactivity. Neither contamination with leukocytes nor higher ATP contents in young erythrocytes appeared to be responsible for this activity in normoblasts and bone marrow. We propose that erythroid precursor cells possess proteolytic activity that is markedly diminished in mature cells. This activity serves an important control function in the regulation of hemoglobin synthesis. It accounts at least in part for the more balanced synthesis of alpha- and beta-chains observed in bone marrow than in peripheral blood in heterozygous beta-thalassemia. It also plays a fine-tuning role in maintaining balanced synthesis in non-thalassemic erythrocytes.

Adenosine Triphosphate↗
PubMed1993

Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis.

Erythropoietin regulates the proliferation and differentiation of erythroid precursor cells. Its effect is mediated by the erythropoietin receptor (EPOR), a member of a large family of cytokine receptors. The EPOR gene has recently been cloned, sequenced, and characterized. As shown experimentally, its intracellular C-terminal part contains a domain exerting negative control on erythropoiesis. Here we describe a G to A transition in nucleotide 6002 of the EPOR gene that converts a TGG codon for tryptophan into a TAG stop codon, predicting the truncation of the 70 C-terminal amino acids of the EPOR molecule. The mutation occurs in heterozygous form in the germ-line DNA of members of a large kindred in which primary erythrocytosis is segregating as a mild autosomal dominant trait. The mutation cosegregates with the disease phenotype in all 29 affected family members studied; it occurs in no unaffected family members or unrelated controls. This appears to be an example of a human condition caused by an EPOR mutation. Striking similarities exist between the human phenotype described here and phenotypes of cell lines expressing similarly truncated EPOR molecules produced experimentally. By analogy with these in vitro studies, one can hypothesize that the truncated EPOR molecules are activated by suppression of phosphorylation leading to loss of the down-modulation exerted by intact EPOR molecules. Experimental modifications of the EPOR gene may eventually have therapeutic applications.

Base Sequence↗
PubMed1993

Identification of a domain required for oncogenic activity and transcriptional suppression by v-erbA and thyroid-hormone receptor alpha.

v-erbA, a mutated version of the chicken thyroid hormone (TH) receptor type alpha, can inhibit hormonal induction of target genes. In addition, v-erbA acts as a constitutive repressor of the basal promoter activity. In vivo, v-erbA can arrest the differentiation of erythroid precursor cells and suppresses transcription of erythrocyte-specific genes. We show that the v-erbA protein of the transformation-defective avian erythroblastosis virus mutant (AEVtd359) fails to suppress basal transcription level and exhibits impaired ability in antagonizing the TH and retinoic acid response. The inactivating mutation is a 1-nt change leading to a Pro-->Arg replacement in the "hinge region" of v-erbA protein. Introducing this mutation in the context of TH receptor alpha selectively inactivates the suppressor function, while hormone-binding and transcriptional-activation properties are unaffected. These data suggest that trans-repression rather than a dominant negative block of TH-receptor or retinoic acid-receptor activation may represent the primary molecular property underlying erbA oncogenesis.

Alpharetrovirus↗
PubMed1983

Monoclonal antibody to human eosinophils recognizing 95 kD surface membrane antigen.

Mice were immunized with purified eosinophils obtained from patients with the idiopathic hypereosinophilic syndrome. A hybridoma initially producing an IgM antibody which switched to an IgG1 antibody was selected for cloning and further testing. This IgG1 antibody reacted with human eosinophils, granulocytes, monocytes and large granular lymphocytes, but did not react with T lymphocytes, B lymphocytes, platelets, erythrocytes, or a panel of human leukemia cells and cell lines. Bone marrow analysis revealed staining of myeloid precursor cells but not erythroid precursors or plasma cells. This IgG1 antibody had no effect on aggregation of granulocytes, lysozyme release, superoxide production, chemotaxis, or killing activity; however, there was some stimulation of beta-glucuronidase secretion. While the antibody did not augment the killing of Staphylococcus aureus by granulocytes, the antibody itself was bactericidal. By immunoprecipitation of granulocytes, eosinophils and monocytes, a molecule with a molecular weight of 95 kD was identified.

Animals↗
PubMed1990

Interferon-gamma modulates fetal hemoglobin synthesis in sickle cell anemia and thalassemia.

Interferon-gamma (IFN-gamma) has been shown to influence globin gene expression in cord blood and normal adult progenitor-derived erythroblasts. To explore the influence of IFN-gamma on fetal hemoglobin (HbF) synthesis in the hemoglobinopathies, erythroid progenitors (BFU-E, burst forming unit-erythroid) from patients with sickle cell anemia (SCA) and thalassemia were co-cultured with or without IFN-gamma. Hemoglobin content in progenitor-derived erythroblasts was assessed by radioligand assay (RIA). Co-culture of erythroid progenitors from 12 SCA patients with 200-400 U/ml of IFN-gamma resulted in a significant decrease in picograms of HbF and percent HbF per BFU-E-derived erythroblast. The mean decrease (+/- SEM) of picograms of HbF per cell and percent of HbF was by 42 +/- 9% and 35 +/- 8% of control cultures, respectively. Co-culture of erythroid progenitors from 10 patients with thalassemia major or thalassemia variant (HPFH/thalassemia, sickle/beta 0-thalassemia) with 200 U/ml IFN-gamma also resulted in a significant decrease in picograms and percent of HbF per BFU-E-derived erythroblast. IFN-gamma treatment also inhibited the enhancement in gamma-globin synthesis induced in culture by butyric acid. Erythroid progenitors from 2 patients with SCA, 1 patient with sickle/beta 0-thalassemia, and 1 patient with HbE/beta 0-thalassemia were co-cultured with IFN-gamma, L-alpha-amino-n-butyric acid, or both. HbF content (expressed as picograms HbF/cell) was decreased in samples co-cultured with IFN, increased in cultures with L-alpha-amino-n-butyric acid, but remained at control values in cultures treated with IFN plus L-alpha-amino-n-butyric acid. These data demonstrate that IFN-gamma is an environmental factor that influences gamma-globin gene expression in the beta hemoglobinopathies in vitro.

Aminobutyrates↗
PubMed1975

Friend leukemia: rapid development of erythropoietin-independent hematopoietic precursors.

Infection of mice with the polycythemia-inducing strain of Friend leukemia virus caused a rapid emergence of new erythroid precursor cells. These cells which, in the absence of erythropoietin, proliferated in vitro to form colonies and even differnetiated, quickly out-numbered the usual erythropoietin-dependent hematopoietic elements in bone marrow and spleen. Ultimately, the marrow and spleen were probably totally repopulated with this erythropoietin-independent cell.

Animals↗
PubMed2001

Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture.

Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system (CNS). However, little is known about expression of EPO and EPO receptor (EPOR) in human CNS tissues. In the present study, we investigated the effects of proinflammatory cytokines on EPO and EPOR expression in highly purified cultures of human neurons, astrocytes, microglia, and oligodendrocytes using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). EPO mRNA was demonstrated only in human astrocytes, while EPOR expression was found in human neurons, astrocytes, and microglia. Neither EPO nor EPOR expression was found in oligodendrocytes. In human astrocytes, EPO mRNA and secreted EPO protein levels were downregulated after exposure to proinflammatory cytokines (IL-1beta, IL-6, or TNF-alpha). In human neurons, TNF-alpha treatment markedly increased EPOR expression. These results suggest that proinflammatory cytokines regulate expression of EPO and EPOR in human neurons, astrocytes, and microglia and further facilitate interactions among different cell types in the human CNS.

Astrocytes↗
PubMed1986

Characterisation of chicken erythroid nuclear proteins which bind to the nuclease hypersensitive regions upstream of the beta A- and beta H-globin genes.

Chicken erythrocyte sequence-specific nuclear DNA-binding proteins, which bind to the 5'-flanking DNAseI hypersensitive sites of the erythrocyte chromosomal beta A- and beta H-globin genes, have been fractionated by HPLC gel filtration. Three beta A-globin gene DNA binding activities (to sites A, B and B' (10-12)) were separated. The erythroid precursor cell line HD3 has beta A-globin gene sites B and B' binding activities, but binding to site A is detected only after the HD3 cells are induced to differentiate. The fractionated protein binds to a redefined site B', which contains at its center the globin CACCC consensus sequence. The chromosomal beta H-globin gene has two 5'-flanking DNAseI hypersensitive sites which bracket two sequences (H and H') bound by erythrocyte and HD3 nuclear protein in vitro. The beta H- and beta A-globin gene binding sites (H and B) contain variants of the sequences bound by Nuclear Factor 1 and the TGGCA-binding protein, and their protein binding activity(ies) co-purify after HPLC gel filtration.

Animals↗
PubMed2006

BP1 is a negative modulator of definitive erythropoiesis.

Beta protein 1 (BP1), a human homeotic transcription factor, is expressed during hematopoeisis in the erythroid lineage. To determine the in vivo role of BP1 in erythropoiesis, we have undertaken two complementary approaches using enforced BP1 expression in both transgenic mice and embryonic stem (ES) cells. Despite repeated attempts, only one adult transgenic BP1 founder mouse among 121 mice was obtained. This mouse presumably survived due to transgene mosaicism because the transgene could not be transmitted. This mouse expressed BP1 and displayed splenomegaly, extramedullary erythropoiesis and severe amyloidosis A in the kidney, a phenotype compatible with thalassemia. Consistently, the presence of BP1 transgene in fetuses was associated with paleness and lethality. In ES cells, BP1 expression in primary differentiation appeared to antagonize adult beta-globin expression. In secondary differentiation, BP1 expression reduced significantly beta-globin gene expression in both primitive and definitive erythroid cells, whereas it impaired only the definitive erythroid cell differentiation. These studies showed that BP1 can negatively modulate adult beta-globin gene expression and definitive erythroid cell differentiation, and suggest that BP1 could play a role in thalassemia.

Amyloidosis↗
PubMed1985

Primary refractory anemia: clinical and laboratory study of erythropoiesis in 16 patients.

Erythropoiesis was studied in vitro in 16 selected patients with primary refractory anemia without excess of blasts who have been followed for an average of 4.8 years. The number of erythroid colonies and bursts grown in vitro from the patients' marrows did not correlate with any parameter of their disease or their prognosis. The response of marrow erythroid precursor cells to erythropoietin was found to be normal. In no case was a serum or IgG inhibitor of erythropoiesis detected either by quantitation of heme synthesized by marrow cells or by the erythroblast cytotoxicity assay. A clinically significant response of the anemia to corticosteroids was noted in three out of 14 patients. Ten patients died during the followup period, eight of them as a consequence of their hematologic disorder. Bone marrow aplasia with pancytopenia developed in six cases, increased number of marrow blasts in two cases, myelofibrosis with myeloid metaplasia in one case and a spontaneous remission in another case. Refractory anemia without excess of blasts is a heterogeneous disorder with variable natural history including evolution into marrow aplasia.

Adult↗
PubMed1991

Pharmacologic purging of malignant T cells from human bone marrow using 9-beta-D-arabinofuranosylguanine.

Arabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate, resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia. In this report, we demonstrate that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 microM araG for 18 hr, up to 6 logs of clonogenic T cells could be eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We discuss the use of this agent in ex vivo elimination of residual malignant T cells from marrow of patients requiring myeloablative chemotherapy with autologous bone marrow rescue.

Antineoplastic Agents↗
PubMed1992

Recurrent granulocytic aplasia as clinical presentation of a persistent parvovirus B19 infection.

We report a case of persistent infection with human parvovirus B19 (PVB19), manifesting clinically as recurrent agranulocytosis and in bone marrow biopsy as recurrent pure granulocytic aplasia. Persistence of parvovirus infection was documented by the presence of PVB19 DNA and anti-PVB19-IgM antibodies in the serum for a period of 19 months. Granulocytic aplasia occurred only when anti-PVB19-IgG antibodies were not detectable in the serum and granulopoiesis showed immediate recovery with high dose intravenous immunoglobulin treatment. This case report suggests that the erythroid precursor cell may not be the only target cell of PVB19 infection. We suggest testing for active parvovirus infection in cases of aplasia of any lineage of the haematopoietic system.

Aged↗
PubMed1993

The bone marrow in murine AIDS.

In order to increase the understanding of blood cytopenias in HIV infection we have investigated the bone marrow in murine AIDS. C57BL/6 mice infected with the LP-BM5 retrovirus show a decrease in cellularity, numerous haemophagocytic histiocytes, a reduction of all erythroid precursor cells, an increase in eosinophil number and an increase in lymphocytes. Immunostaining with an anti-Pr60gag antibody shows that the majority of bone marrow cells express the viral protein. Thus, the bone marrow in MAIDS has many similarities with the bone marrow from patients with advanced AIDS and may prove useful as a model for therapy aimed at treating blood cytopenias.

Animals↗
PubMed1994

Circulating cytokines in sickle cell patients during steady state.

Plasma levels of GM-CSF, IL-3, IL-6 and IL-1 (alpha,beta) were investigated in steady-state sickle cell patients. We find that SS patients with low levels of HbF (< 9% [LFSS]) are characterized by elevated plasma GM-CSF, whereas in patients with high levels of HbF (HFSS), GM-CSF is not detectable. In contrast, HFSS patients exhibited increased plasma IL-3 (m = 84.8 +/- 57 pg/ml), whereas LFSS patients had lower or no detectable plasma IL-3, IL-1(alpha,beta) and IL-6 were also detected in plasma from some SS patients, but there was no correlation with HbF levels. Normal controls tested negative for all cytokines, except for one individual positive for IL-3. These results are compatible with a model in which the level of haemopoietic stress determines the level of participation of GM-CSF or IL-3 in the regulation of SS circulating BFU-E.

Adult↗
PubMed1992

Clinical and histopathological features of parvovirus B19 infection in the human fetus.

OBJECTIVE: To provide a comprehensive description of the clinical and histopathological features associated with parvovirus B19 infection of the human fetus. SUBJECTS: All cases of parvovirus B19-related fetal death presenting to the John Radcliffe Hospital, Oxford, over a 16 year period. Diagnosis was confirmed retrospectively by non-isotopic in situ hybridization for parvovirus B19 DNA. RESULTS: The ten cases occurred in two clusters (1979-80 and 1988-89) and presented between 15 and 29 weeks gestation. In at least three cases maternal infection was asymptomatic. Nine fetuses were grossly hydropic at necropsy. Histological features common to all cases included the presence of typical intranuclear inclusions in erythroid precursor cells and evidence of vasculitis within placental villi. Inflammatory changes were also present in the myocardium of four cases, with evidence of subendocardial fibroelastosis in three. CONCLUSIONS: Histological features of fetal parvovirus B19 infection are similar across a range of gestational ages. The heart failure and hydropic state associated with fetal parvovirus infection may be of multifactorial aetiology, and not due to fetal anaemia alone.

Adult↗