Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations at the murine dominant-white spotting locus (W) (c-kit) affect various aspects of hematopoiesis. We have made antibodies against c-Kit with the synthetic peptides deduced from the murine c-kit gene and examined the role of c-Kit in erythropoiesis. The antibody inhibited the stromal cell-dependent large colony formation of the erythroid progenitors. In the culture of erythropoietin-responsive erythroid progenitors of the anemia-inducing Friend virus-infected mouse spleen, the antibody inhibited only proliferation, but not differentiation of the progenitor cells. The inhibition was effective only at the early phase (within 6 hours after erythropoietin addition) before the cells start to proliferate induced by erythropoietin. During the early phase, erythropoietin down-regulated c-kit gene expression. These results suggest a mechanism of combined action of c-Kit with erythropoietin on the lineage-restricted erythroid progenitor cells.
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PMID:Combined action of c-kit and erythropoietin on erythroid progenitor cells. 137 12

Mutations in the Steel locus, encoding a growth factor (Steel factor or SF) or c-kit, the gene encoding its receptor, result in severe anemia in the mouse. In the present study, we have addressed the mechanism of synergistic growth activation, at the cellular level, by SF and GM-CSF using the blast cells of acute myeloblastic leukemia (AML blasts). Our data indicate that SF drastically alleviates the requirement in cell interaction for blast colony formation in most of the samples tested. Analysis of cultures performed in the presence of SF and GM-CSF at different cell concentrations, ranging from 1,000 to 20,000 cells, suggested a single limiting element, i.e., the blast clonogenic cell, while 2 or more limiting elements were found in cultures stimulated with GM-CSF alone, suggesting interacting cell populations. The presence of membrane-bound SF was detected by immunofluorescence, suggesting the possibility that secreted or membrane-bound SF may, at least in part, contribute to the density-dependent growth of AML blasts. In all samples tested, SF appears to increase the responsiveness of AML blasts to GM-CSF, as demonstrated by a 3-fold decrease of GM-CSF half efficient concentration on addition of SF to the cultures. Exposure of AML blasts to SF did not affect GM-CSF receptor expression, suggesting that this increase in GM-CSF responsiveness is likely to occur at the postreceptor level. Interestingly, 2 of 15 AML samples surveyed did not respond to SF, and were both of the myelomonocytic or monocytic subtype, classified as M4 and M5, respectively.
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PMID:Product of the Steel locus can replace leukemic cell interaction. 138 39

Mutations at the dominant white spotting (W) and Steel (Sl) loci in mouse exert deleterious effects on three migratory cell lineages (primordial germ cells, melanocytes and hematopoietic stem cells) resulting in loss of pigmentation, reduced fertility and anemia. The W locus encodes the c-kit protein tyrosine kinase (TK) receptor. More recently, the Sl locus has been shown to encode a ligand for c-kit, which is variously known as mast cell growth factor (MGF), stem cell growth factor and c-kit ligand. Here we report an in situ hybridization analysis comparing the expression profiles of MGF and c-kit transcripts during mouse embryogenesis. The data are consistent with the c-kit receptor-ligand complex providing a homing mechanism during stem cell migration in early development and in stem cell proliferation, differentiation, or survival in late development. In the nervous system, an unexpected and complex pattern of expression is uncovered that suggests involvement of the W and Sl gene products in the organization of the neural tube and brain.
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PMID:Embryonic RNA expression patterns of the c-kit receptor and its cognate ligand suggest multiple functional roles in mouse development. 171 75

Mice with W mutations characterized by hypopigmentation, sterility, anemia, and mast cell deficiency have abnormalities in c-kit, a receptor with tyrosine kinase activity. Recently, the ligand for c-kit was cloned by investigators in several laboratories. Zsebo et al identified and cloned a gene for a cytokine termed stem cell factor (SCF) in the medium conditioned by buffalo rat liver cells, and this cytokine proved to be c-kit ligand. We have examined the effects of recombinant rat SCF (rrSCF) on colony formation from primitive hematopoietic progenitors in culture. rrSCF and erythropoietin (Ep) supported formation of granulocyte/macrophage (GM) colonies as well as a small number of multilineage and blast cell colonies from marrow cells of normal mice. We then examined the effects of rrSCF using marrow and spleen cells of mice that had been treated with 150 mg/kg 5-fluorouracil (5-FU). Unlike single factors, combinations of factors such as rrSCF plus interleukin-3 (IL-3), rrSCF plus IL-6, and rrSCF plus granulocyte colony-stimulating factor (G-CSF) markedly stimulated the growth of multilineage colonies. In contrast to these factor combinations and a combination of IL-3 and IL-6, a combination of rrSCF and IL-4 did not support multilineage colony formation. Mapping studies of the development of multipotential blast cell colonies further indicated that rrSCF, like IL-6, G-CSF, and IL-11, shortens the dormant period in which the stem cells reside. When we tested the effects of rrSCF using pooled blast cells, which are highly enriched for progenitors and are devoid of stromal cells, rrSCF plus Ep supported formation of only a few multilineage colonies, indicating that rrSCF itself is ineffective in support of the proliferation of multipotential progenitors. However, rrSCF supported formation of a significant number of neutrophil and neutrophil/macrophage colonies from pooled blast cells, indicating that rrSCF is able to support directly the proliferation of progenitors in neutrophil/monocyte lineages. c-kit ligand may play important roles in adult hematopoiesis.
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PMID:Enhancement of murine blast cell colony formation in culture by recombinant rat stem cell factor, ligand for c-kit. 171 19

The protooncogene c-kit is critical for development of hematopoietic stem cells, germ cells, and melanoblasts in the mouse. Homozygous mutations of this gene in the mouse cause anemia, infertility, and albinism, whereas heterozygous mutant mice usually exhibit only a white forehead blaze and depigmentation of the ventral body, tail, and feet. The heterozygous mouse phenotype is very similar to human piebald trait, which is characterized by a congenital white hair forelock and ventral and extremity depigmentation. To investigate the possibility that alterations in the human c-kit gene may be a cause of piebald trait, DNA from seven unrelated affected individuals was examined by Southern blot analysis. One subject, although cytogenetically normal, has a heterozygous deletion of the c-kit protooncogene. This deletion encompasses the entire coding region for c-kit and also involves the closely linked gene for platelet-derived growth factor receptor alpha. Fluorescence in situ hybridization of genomic c-kit probes to metaphase chromosomes independently confirmed the deletion in this case. These findings provide molecular evidence mapping piebald trait to the c-kit locus on chromosome 4. Although we cannot exclude the involvement of other closely linked genes, the demonstration of a genomic c-kit deletion in one subject with piebald trait and the marked concordance of the human and mouse phenotypes provide strong evidence for the role of c-kit in the development of human melanocytes and in the pathogenesis of piebald trait.
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PMID:Deletion of the c-kit protooncogene in the human developmental defect piebald trait. 172 May 53

Mouse strains carrying mutations at the Dominant White Spotting (W) locus or the Steel (Sl) locus are anemic and display defects in pigmentation and gametogenesis. In W mutants the anemia is due to a deficiency of hemopoietic stem cells and, in Sl mutants, to a deficiency of supporting stromal cells in the bone marrow. The W locus encodes the c-kit proto-oncogene product, a cell surface receptor with protein-tyrosine kinase activity, and the Sl locus encodes its ligand, a hemopoietic cytokine known variously as Steel factor (SLF), mast cell growth factor, stem cell factor, and Kit ligand. SLF can synergize with a number of other cytokines to stimulate growth of hemopoietic progenitors in vitro and stimulates blood cell production in vivo in animals. Here we review the biological activities of SLF, with particular emphasis on its effects on hemopoietic stem and progenitor cells. We also discuss present knowledge of the molecules involved in SLF-triggered signal transduction, and speculate on potential therapeutic applications for SLF in human disease.
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PMID:The kit receptor and its ligand, steel factor, as regulators of hemopoiesis. 172 56

Mutations at the W locus in the mouse have pleiotropic effects on embryonic development and hematopoiesis. The characteristic phenotype of mutants at this locus, which includes white coat color, sterility, and anemia, can be attributed to the failure of stem cell populations to migrate and/or proliferate effectively during development. Mapping experiments suggest that the c-kit proto-oncogene, which encodes a putative tyrosine kinase receptor, is a candidate for the W locus. We show here that the c-kit gene is disrupted in two spontaneous mutant W alleles, W44 and Wx. Genomic DNA that encodes amino acids 240 to 342 of the c-kit polypeptide is disrupted in W44; the region encoding amino acids 342 to 791 is disrupted in Wx. W44 homozygotes exhibit a marked reduction in levels of c-kit mRNA. These results strongly support the identification of c-kit as the gene product of the W locus.
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PMID:The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. 245 42

Stem cell factor (SCF) promotes the growth of multilineage hematopoietic cells. SCF is a product of the steel (Sl) locus of the mouse, and it is a ligand for the c-kit proto-oncogene receptor. Previous studies have investigated the distribution of SCF mRNA in developing and adult tissues of the rat, including the brain. However, there have been conflicting reports on the distribution of SCF mRNA in adult rat brain. Specially noteworthy was one report of the absence of SCF mRNA in adult hippocampus, while another group reported the presence of that mRNA in the dentate gyrus of the hippocampus. We conducted this study to determine the precise localization of SCF mRNA in adult brain, and were especially interested in determining whether that mRNA is localized in adult hippocampus. We used in situ hybridization histochemistry to demonstrate that the gene encoding SCF is actively expressed in neuron-like cells in various regions of adult rat brain. Our data show that SCF mRNA is present in neuron-like cells in the thalamus, cerebral cortex, cerebellum, and hippocampus, particularly in the dentate gyrus, but also in CA1, CA2, and CA3. We did not localize SCF mRNA in glia-like cells. Dyskeratosis congenita is a severe human disorder, associated with dyskeratosis, anemia, and mental retardation. It has been postulated that dyskeratosis congenita is due to a deficiency in SCF function. It is unknown why patients with dyskeratosis congenita suffer from mental retardation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization of stem cell factor mRNA in adult rat hippocampus. 748 32

In order to clarify the role of haematopoietic stem and progenitor cells in bone-marrow toxicity induced by 1,3-butadiene, we examined the effects of its primary metabolite, 3,4-epoxybutene, on the cytokine response of these cells from C57B1/6 mice. Pretreatment with epoxybutene in vitro suppressed recombinant interleukin-3-stimulated colony formation in haematopoietic stem and progenitor cells, had no effect on colony formation with recombinant granulocyte/macrophage-colony stimulating factor or recombinant granulocyte-colony stimulating factor alone, and completely blocked the synergism of recombinant c-kit ligand and granulocyte/macrophage colony stimulating factor. Butadiene-induced leukaemogenesis, macrocytic anaemia and thymic atrophy are reminiscent of the conditions observed in mice bearing mutations at the W or Sl loci, which are deficient in the c-kit receptor and c-kit ligand, respectively. Epoxybutene did not suppress colony formation in cells from W/Wv and Sl/Sld mice, consistent with the absence of the population of haematopoietic stem and progenitor cells that is susceptible to butadiene in those genetically deficient strains. These findings indicate that the pathological conditions observed after either exposure to butadiene or W or Sl mutations are due to a functional defect in a subpopulation of primitive haematopoietic stem and progenitor cells that plays a major role in the pathogenesis of both T-cell leukaemia/lymphoma and anaemia in the mouse.
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PMID:Toxicity of 1,3-butadiene to bone marrow mimics haematopoietic defects observed in mice bearing white spotted or steel mutations. 752 Aug 86

Although IL-12 has been reported to synergize with c-kit ligand (KL) in promoting hematopoietic stem cell proliferation in vitro, administration of recombinant mouse IL-12 (rIL-12) to normal mice caused a dose- and time-dependent anemia, leukopenia, and thrombocytopenia in vivo. Decreased numbers of bone marrow cells were recovered from the tibiae of IL-12-treated mice, and histologic examination of the marrow revealed a loss of mature neutrophils and red blood cell precursors. However, simultaneously with the suppression of hematopoiesis in the bone marrow, the IL-12-treated mice developed splenomegaly, which was largely caused by a marked enhancement of splenic extramedullary hematopoiesis of the erythroid, myeloid, and megakaryocytic lineages. These histologic observations were confirmed by colony-forming cell assays in which administration of IL-12 was shown to cause a time-dependent decrease in bone marrow CFU-GM, CFU-E, and BFU-E hematopoietic colony-forming cells while causing an increase in splenic CFU-GM and BFU-E colony-forming cells. All these effects were reversible upon cessation of IL-12 treatment. The observation that in IL-12-treated mice hematopoiesis was suppressed in the marrow but enhanced in the spleen suggests that myelosuppression was not caused by a direct effect of IL-12 on hematopoietic progenitors. It seems likely that myelosuppression was caused instead by an IL-12-induced alteration in the local environment of the marrow.
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PMID:Administration of recombinant interleukin-12 to mice suppresses hematopoiesis in the bone marrow but enhances hematopoiesis in the spleen. 762 13


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