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 of c-kit, which encodes a transmembrane receptor tyrosine kinase, have been identified in mice by abnormal coat color, anemia, and germ cell defects. Mice heterozygous for mutations of c-kit have a white forehead blaze and a white ventral spot, leading these mutants to be termed dominant White spotting (W). We have previously demonstrated that the membrane-associated isoform of human stem cell factor (hSCF220, the ligand for c-kit) is inefficiently processed in murine stromal cell transfectants. Thus, in murine cell lines analyzed in vitro, hSCF220 transfectants present SCF as a membrane restricted protein in contrast to the murine SCF220 cDNA protein product, which is slowly cleaved and secreted. We show here that transgenic mice expressing the human SCF220 isoform in vivo display a phenotype indistinguishable from some alleles of W. Specifically, hSCF220-expressing transgenic mice display a prominent forehead blaze and a white ventral spot. Generations of doubly heterozygous animals that carry both a mutated c-kit allele and the hSCF220 transgene display a more severe coat color abnormality. This phenotype appears to be due to occupancy of murine c-kit by human SCF and diminished cell surface expression of endogenous murine SCF. Normal signaling events that lead to cell survival or proliferation appear to be disrupted in vivo in these transgenic mice.
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PMID:Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations. 860 35

Investigating 208 patients with acute haematological malignancies, we found that stem cell factor receptor (SCFR) was expressed on high numbers of blast cells from the vast majority of patients (93%) with refractory anaemia with excess of blasts in transformation. SCFR was also detected in 62% of AMLs, in which it was directly associated to the expression of CD7, interleukin 6 receptor and CD34, and inversely to that of CD11b and CD14. SCFR-positive cases were preferentially represented in AML-M1 (70%) and in AML-M2 (83%) subsets, whereas only 45% of the remaining samples (M3-M4-M5) exhibited SCFR positively. Interestingly, 50% of cases with acute promyelocytic leukaemia expressed SCFR and this molecule was heterogenously regulated by in vitro treatment with all-trans retinoic acid.
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PMID:Stem cell factor receptor (c-kit, CD117) is expressed on blast cells from most immature types of acute myeloid mallignancies but is also a characteristic of a subset of acute promyelocytic leukaemia. 861 17

Recombinant cytokines such as stem cell factor (SCF) are currently being tested for the ability to ameliorate 3'azido-3'deoxythymidine (AZT) induced anemia in AIDS patients. Recently, we demonstrated that SCF and hemin in vitro greatly increased the resistance of burst-forming units erythroid (BFU-E) to AZT. We therefore attempted to ameliorate AZT-induced anemia in vivo using SCF and hemin in immunodeficient LP-BM5 infected (MAIDS) mice. SCF and hemin were administered with oral AZT for 3 wk and the effects on erythropoiesis examined. Hemin significantly increased hematocrits of AZT-treated mice and control mice. However, SCF and SCF-hemin combinations failed to raise hematocrits. Reticulocyte numbers were significantly consistently increased only in hemin-treated mice receiving AZT. The numbers of CFU-E were increased in bone marrow of AZT-treated mice receiving hemin. Therefore, SCF did not enhance the erythropoietic effect of hemin in AZT-treated immunodeficient mice.
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PMID:Effects of combinations of stem cell factor and hemin on erythropoiesis after azidothymidine treatment of immunosuppressed mice. 885 89

Myeloid cells arise from a common stem cell whose development is regulated by stimulatory and inhibitory growth factors. Pluripotential hematopoietic stem cells are most influenced by IL-3, GM-CSF, and stem cell factor while committed progenitor cells are regulated by variable concentrations of GM-CSF, G-CSF, M-CSF, IL-5, Epo, and Tpo. As a result of their common origin, a key point to remember about myeloproliferative disorders is the involvement of multiple cell lines in dysplastic and neoplastic conditions. Dysplastic changes may signal early neoplastic changes with cases progressing to acute leukemia. Myelodysplastic syndrome (MDS) is associated with anemia or multiple cytopenias, normal to hypercellular bone marrow, ineffective hematopoiesis, and less than 30% blast cells of all nucleated cells in the bone marrow. Chronic myeloid leukemias also have less than 30% blast cells of all nucleated cells in the bone marrow and are distinguished from MDS by elevated cell counts of one or more cell lines with mature forms predominating. Acute myeloid leukemias, often the end result of all myeloproliferative disorders, are recognized by equal or greater 30% blast cells of all nucleated cells in the bone marrow. Additional diagnostic information from cytochemical stains, immunohistochemical staining, and cytogenetic analysis can influence the final diagnosis when morphology alone is equivocal. In conclusion, prognosis and response to treatment are best determined by application of a uniform set of standards in evaluating hematolymphatic neoplasia. Critical to diagnosis are complete blood and bone marrow evaluations including observation for dysplastic changes and blast cell quantitation. In addition, evidence for tissue infiltration identified through cytologic or histologic evaluations of lymph node, spleen, or liver is recommended.
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PMID:Myelopoiesis and myeloproliferative disorders. 886 89

The c-KIT proto-oncogene encodes for a transmembrane receptor and is associated with maturation of several cell types, including germ cells. The ligand of the receptor has been identified as stem cell factor (SCF). Loss or alteration of the expression of either of these factors leads to anemia, albinism, and/or sterility in mice. We examined the expression of c-KIT and SCF by immunohistochemistry in specimens from normal and infertile human testis. All specimens were obtained in the evaluation of male subfertility. We were able to demonstrate staining for c-KIT in Leydig cells in all specimens. Normal testis stained for c-KIT in the cytoplasm of early spermatogenic cells, as well as the acrosomal granules of the round spermatids and the acrosome of testicular spermatozoa. However, staining in testis demonstrating maturation arrest failed to demonstrate acrosomal staining, and Sertoli-only specimens demonstrated staining for c-KIT in Leydig cells only. The results for SCF demonstrated an overall uniform staining of Leydig cells in all specimens. The intensity of staining of Sertoli cells increased from normal to maturation arrest to Sertoli-only specimens. Germ cell staining was consistently negative. We hypothesize that these staining patterns for SCF are due to either lack of staining of the receptor-ligand complex or overexpression of the kit ligand in tissue that does not express the kit receptor. It appears that the c-kit receptor is expressed in the acrosome of developing germ cells, as well as in Leydig cells and early spermatogenic cells, suggesting a role in the acrosome reaction, as well as germ cell maturation and differentiation.
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PMID:Expression of c-KIT and its ligand, stem cell factor, in normal and subfertile human testicular tissue. 888 3

Diamond-Blackfan anemia (DBA) is a congenital pure red blood cell aplasia diagnosed in the first year of life. Familiarity is apparent in 10% of patients, with all other cases being sporadic. Physical abnormalities are present in at least one third of patients, pointing to a defect in early embryo development. The main clinical sign is profound isolated anemia, with normal numbers and functioning of the other hemopoietic cells. Reticulocyte counts are very low. Bone marrow reflects defective erythropoiesis, showing a very low number of erythropoietic precursors and a reduction of BFU-E progenitor cells. Proliferation and differentiation of the other lineages are normal. The very high erythropoietin (EPO) levels are usually not proportionate to the level of anemia and reflect relative EPO insensitivity, which is also apparent in vitro. Conversely, erythroid progenitors from DBA patients also show a defective or incomplete response to other erythropoietic growth factors, such as IL-3 or IL-6. A significant response has been observed in vitro to stem cell factor in many, but not all patients. Many patients respond clinically to corticosteroids and some develop hematologic remissions, both after corticosteroids and spontaneously. Patients who do not respond to corticosteroids and those who have to discontinue treatment because of side effects must rely on chronic transfusion and are thus exposed to all its complications. Bone marrow transplantation has been performed in some individuals, usually with a successful outcome. This suggests a normal marrow microenvironment and rules out the hypothesis of defective stromal cell function. The variable clinical and biological patterns may be the expression of multiple etiologies or represent variable expressivity of a single genetic defect. Only identification of the responsible gene(s) will solve this question. Growth factors exerting an effect on erythropoiesis (and relative receptors) or transacting proteins which regulate their expression are likely candidates in the hunt for a causal gene.
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PMID:Diamond-Blackfan anemia: a congenital defect in erythropoiesis. 900 45

The unstimulated and induced production of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), IL-3, IL-6, stem cell factor (SCF), IL-1beta, tumour necrosis factor-alpha (TNF-alpha), TNF-beta, interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) was determined after culture of blood mononuclear cells from 22 patients with severe beta-thalassaemia in a regular transfusion programme, five non-regularly transfused patients with beta-thalassaemia intermedia and nine normal persons. A distinct pattern of cytokine production in thalassaemic patients was detected, namely a low unstimulated production of all cytokines and a significant increase in the stimulated production of IFN-gamma, TNF-alpha and IL- 1beta; these abnormalities were more pronounced in the more heavily transfused older patients. The increased production of the above cytokines, which usually characterize the acute response to infectious agents and have a negative effect on erythropoiesis, may explain the deterioration of anaemia found in thalassaemic patients during acute infections.
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PMID:A distinct pattern of cytokine production from blood mononuclear cells in multitransfused patients with beta-thalassaemia. 906 38

The purpose of the present study was to measure serum concentrations of stem cell factor (SCF) and interleukin-3 (IL-3) in patients with acute Plasmodium falciparum malaria. Serum samples from 15 patients were taken on day of admission and days 7, 14, 21, and 28. Anemia developed in 80% of patients. A transient increase in IL-3 could be observed at the beginning of the disease. It remains controversial whether the measured concentrations of IL-3 and SCF correlate with the grade of anemia. The possibly suppressed IL-3 and SCF production may contribute to the prolonged anemia in P. falciparum malaria, as has been shown for erythropoietin.
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PMID:Levels of stem cell factor and interleukin-3 in serum in acute Plasmodium falciparum malaria. 906 61

Mutations of the receptor tyrosine kinase c-kit or its ligand stem cell factor (SCF), which is encoded as a soluble and membrane-associated protein by the Steel gene in mice, lead to deficiencies of germ cells, melanocytes, and hematopoiesis, including the erythroid lineage. In the present study, we have used genetic methods to study the role of membrane or soluble presentation of SCF in hematopoiesis. Bone marrow-derived stromal cells expressing only a membrane-restricted (MR) isoform of SCF induced an elevated and sustained tyrosine phosphorylation of both c-kit and erythropoietin receptor (EPO-R) and significantly greater proliferation of an erythrocytic progenitor cell line compared with stromal cells expressing soluble SCF. Transgene expression of MR-SCF in Steel-dickie (Sld) mutants resulted in a significant improvement in the production of red blood cells, bone marrow hypoplasia, and runting. In contrast, overexpression of the full-length soluble form of SCF transgene had no effect on either red blood cell production or runting but corrected the myeloid progenitor cell deficiency seen in these mutants. These data provide the first evidence of differential functions of SCF isoforms in vivo and suggest an abnormal signaling mechanism as the cause of the severe anemia seen in mutants of the Sl gene.
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PMID:Signaling through the interaction of membrane-restricted stem cell factor and c-kit receptor tyrosine kinase: genetic evidence for a differential role in erythropoiesis. 944 48

We recently showed that a retrovirally transduced prolactin receptor (PrlR) efficiently supports the differentiation of wild-type burst-forming unit erythroid (BFU-e) and colony-forming unit erythroid (CFU-e) progenitors in response to prolactin and in the absence of erythropoietin (Epo). To examine directly whether the Epo receptor (EpoR) expressed by wild-type erythroid progenitors was essential for their terminal differentiation, we infected EpoR-/- progenitors with retroviral constructs encoding either the PrlR or a chimeric receptor containing the extracellular domain of the PrlR and intracellular domain of EpoR. In response to prolactin, both receptors were equally efficient in supporting full differentiation of the EpoR-/- progenitors into erythroid colonies in vitro. Therefore, there is no requirement for an EpoR-unique signal in erythroid differentiation; EpoR signaling has no instructive role in red blood cell differentiation. A synergistic interaction between EpoR and c-kit is essential for the production of normal numbers of red blood cells, as demonstrated by the severe anemia of mice mutant for either c-kit or its ligand, stem cell factor. We show that the addition of stem cell factor potentiates the ability of the PrlR to support differentiation of both EpoR-/- and wild-type CFU-e progenitors. This synergism is quantitatively equivalent to that observed between c-kit and EpoR. Therefore, there is no requirement for an EpoR-unique signal in the synergistic interaction between c-kit and EpoR.
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PMID:The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit. 971 74


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