Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested the ability of recombinant human (rhu) mast cell growth factor (MGF), also known as c-kit ligand, to stimulate the colony formation of human bone marrow cells in semisolid medium alone and in combination with rhu erythropoietin (EPO), rhu Interleukin 3 (IL-3), rhu granulocyte colony stimulating factor (G-CSF) and rhu granulocyte-macrophage colony stimulating factor (GM-CSF). The addition of MGF to cultures containing EPO or EPO + IL-3, GM-CSF and G-CSF, resp., resulted in macroscopic erythroid burst-forming units (BFU-E). Multipotential (colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM]) progenitors were stimulated by MGF in the presence of EPO. Colony-forming unit granulocyte-macrophage (CFU-GM) were activated by MGF only in combination with GM-CSF. The combination of MGF with EPO was used for synergism studies in healthy cynomolgus monkeys. In the chosen concentration MGF alone had no effect on white blood cell (WBC) counts and on platelets, but a slight effect on reticulocytes. EPO by itself increased reticulocyte counts with no effects on WBC or platelets. The combination of both factors resulted in a significant increase of reticulocytes. No other effects were seen. These studies demonstrate the potent synergistic interaction of MGF and other hematopoietic growth factors.
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PMID:Studies on the efficacy of mast cell growth factor (c-kit ligand) in vitro as well as in vivo. 172 1

Recombinant human stem cell factor (SCF) is homologous with recombinant rat SCF (rrSCF) and is a ligand for c-kit. We determined the influence of SCF on hematopoiesis in vitro and in vivo in baboons. In vitro, SCF alone stimulated little growth of hematopoietic colony-forming cells from baboon marrow, but did increase the number of colonies formed in response to erythropoietin (Epo), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In vivo, SCF caused an increase in the peripheral blood of the number of erythrocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. In marrow, it caused an increase in marrow cellularity and in the absolute number of colony-forming unit-granulocyte-monocyte (CFU-GM) and burst-forming unit-erythroid (BFU-E) in marrow following infusion of SCF. The in vivo stimulation of multiple lymphohematopoietic lineages corroborates previous in vitro studies and suggests a potentially important clinical role for SCF.
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PMID:Recombinant human stem cell factor, a c-kit ligand, stimulates hematopoiesis in primates. 191 79

Ligand-induced dimerization is a key step in the activation of receptor tyrosine kinases, including the epidermal growth factor receptor, stem cell factor receptor (c-kit), and colony-stimulating factor 1 receptor (c-fms). The erythropoietin receptor (EPOR), a member of the cytokine receptor family, contains no kinase motif and its activation mechanism remains unclear. Here we show that chimeric receptors carrying the extracellular domain of the epidermal growth factor receptor or c-kit linked to the cytoplasmic domain of the EPOR, transmitted epidermal growth factor or stem cell factor-dependent proliferation signals in an interleukin 3-dependent cell line. The chimeric receptors as well as the wild-type EPOR also mediated the ligand-induced tyrosine phosphorylation of a set of similar proteins. Moreover, erythropoietin triggered mitogenic signals of chimeric receptors carrying the extracellular domain of the EPOR linked to the tyrosine kinase of c-fms. These data demonstrate the interchangeability of domains between two distinct receptor families and suggest that ligand-induced dimerization is a key step in activating the EPOR.
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PMID:Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases. 750 12

Stem cell factor (SCF), the ligand of the c-kit receptor, is a potent enhancing cytokine for haematopoietic cells in the presence of IL-3, GM-CSF and erythropoietin (Epo). In the clonogenic assays of 63 MDS patients, the addition of rh-SCF + GM-CSF and/or IL-3 induced a significant increase (p < 0.001) in the number and size of CFU-GM. Never reaching the levels of controls, this increase was seen in all FAB subtypes, but particularly in RA. There was no significant increase in cluster formation, even in RAEB or RAEBt. Rh-SCF (10 ng/ml) led to mean increases of up to 26 times in the number of Epo-dependent BFU-E colonies, particularly in RA (p < 0.001) and RAEB (p < 0.05). Individual responses varied widely (especially in RA) from no response to supranormal levels. Added to the weekly refeed of 37 MDS LTBMC, SCF (10 ng/ml) induced only a 7% mean increase in both cell output and the number of clonogenic cells recovered in the supernatant. Immunohistochemical examination of the supernatant showed significant increases in differentiating myeloid cells in all examined cases, and in erythroid cells in 3 cases; blast cells increased in only 3 cases. These data suggest that rh-SCF is capable of at least partially reversing defective MDS myeloid haematopoiesis, and leads no overt risk of leukaemic transformation. Its potent effect on erythroid cells is encouraging for future clinical applications in patients, particularly if they are selected by means of in vitro tests.
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PMID:Effects of recombinant human stem cell factor (rh-SCF) on colony formation and long-term bone marrow cultures (LTBMC) in patients with myelodysplastic syndromes. 750 65

The effects of recombinant human stem cell factor (SCF/c-kit ligand), interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) on erythroid colony formation by non-phagocytic mononuclear cells (MNC) and CD34+ cells derived from normal human bone marrow (BM), peripheral blood (PB) and umbilical cord blood (CB) were studied using a methylcellulose culture containing recombinant human erythropoietin (Epo). BM-MNC generated the largest number of total erythroid colonies consisting of erythroid bursts and erythroid mixed colonies (E-Mix) in the presence of SCF, whereas PB-MNC produced the largest number with IL-3. No additive effect between SCF and IL-3 was observed in the erythroid colony formation by BM- or PB-MNC. These observations were reproducible in cultures with several independent samples and purified CD34+ cells, suggesting that in normal human adults the erythroid progenitors supported by SCF alone mainly reside in the BM but those supported by IL-3 alone are mainly circulating. IL-3 was the most potent promoter of the total erythroid colony formation by CB-MNC, but it had no cooperation with SCF. In contrast, SCF supported large numbers of E-Mix and showed significant cooperative activity with IL-3 in E-Mix formation. These findings were also confirmed using independent specimens and CD34+ cells. Outstanding E-Mix formation by the CB cells indicated that newborn infants contain significantly more immature circulating erythroid progenitors than adults. These observations will stimulate interest in the role of the c-kit-SCF system as an adhesion molecule in the ontogenetic development of hemopoiesis.
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PMID:Different responses of human marrow and circulating erythroid progenitors to stem cell factor, interleukin-3 and granulocyte/macrophage colony-stimulating factor. 751 46

The purpose of this study was to define the effects of recombinant human Steel factor (rhSF) (c-kit ligand) on early and late cord blood hematopoietic progenitors. In the presence of recombinant human erythropoietin (rhEpo), rhSF supported the development of granulocyte/macrophage, erythroid, and mixed colonies from CD34-positive cord blood cells. With increasing concentrations of rhSF, an increase in the number of mixed colonies was observed. This increase was paralleled by a decrease in the number of erythroid colonies, such that the total number of the two colony types was always constant. Similar results were observed when CD34+ cells were cultured in the presence of a combination of rhEpo, rhSF, and rhIL-3. These results indicate that the presence of rhSF enhanced the detectability of the nonerythroid components of mixed colonies. The effect of rhSF on early progenitors (pre-colony-forming units [pre-CFU]) was studied in a two-step assay. In this assay, cells positive for CD34 and resistant to treatment with 4-hydroperoxycyclophosphamide (CD34+/4-HCres) were cultured in suspension for 7 days with rhSF, rhIL-3, or rhSF plus rhIL-3 and then plated in clonogenic assays. Before suspension culture, CD34+/4-HCres cells had a low clonogenic potential (0.37%). After being cultured in suspension, however, these cells gave rise to a large number of colonies of all types when replated. Cells cultured in suspension with the combination of rhSF and rhIL-3 increased significantly in number and gave rise to more colonies, when compared to cells cultured with either factor alone (synergistic effect). In identical experiments, such as effect had not been observed with combinations of rhIL-3 and either rhIL-1 or rhIL-6. Thus, rhSF supports the expansion and differentiation of early progenitors in human cord blood.
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PMID:Effects of recombinant human Steel factor (c-kit ligand) on early cord blood hematopoietic precursors. 751 47

In long-term human bone marrow cultures, stromal cells of human origin are usually used on the assumption that human primitive progenitor cells do not respond to cytokines produced by stromal cells from other species. There is accumulating evidence, however, that murine stromal cells also promote maintenance and differentiation of very primitive human stem cells, which suggests the existence of novel stromal activities that cross species barriers. In this study, we show that a murine bone marrow-derived stromal cell line, MS-5, allows the proliferation of the human leukemic cell line UT-7. The long-term growth of UT-7 is usually supported only by human interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoietin (Epo). None of these three cytokines was involved in the observed effect, since murine GM-CSF and IL-3 do not act on human cells and MS-5 cells do not produce Epo. Soluble stem cell factor (SCF) induced UT-7 cell proliferation. However, S1/S1 mutant fibroblasts also supported UT-7 cell growth and anti-c-kit antibodies only partially abolished UT-7 cell proliferative response to MS-5 cells. These observations excluded a major role of SCF in this system. MS-5-derived growth-promoting activity was diffusible, but attempts to grow UT-7 cells in high levels of known soluble murine stromal-derived cytokines active on human cells showed no or minimal response, suggesting that MS-5's proliferative effect was not mediated by known cytokines. Finally, involvement of an autocrine loop of activation induced by MS-5 was excluded: RT-PCR analysis did not detect increased transcripts for GM-CSF, IL-3, IL-6, SCF, or Epo in UT-7 cells cocultured for 2 to 6 days with MS-5. In addition, UT-7 cell proliferation on MS-5 was not inhibited by neutralizing antibodies against the human GM-CSF receptor or the human IL-6 receptor alpha chain. Whether UT-7 cell proliferation triggered by MS-5 reflects the existence of novel stromal cytokines or results from synergistic interactions on the MS-5 cell surface between extracellular matrix proteins and cytokines will require further investigation.
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PMID:A murine stromal cell line promotes the proliferation of the human factor-dependent leukemic cell line UT-7. 751 51

In vitro growth of primitive hematopoietic progenitors is severely impaired in the myelodysplastic syndromes (MDS). To determine if the c-kit ligand mast cell growth factor (MGF) can improve progenitor growth in MDS, we evaluated in vitro responsiveness of bone marrow progenitors from 25 patients to MGF and/or GM-CSF, interleukin-3 (IL-3) and PIXY 321, and examined the relationship between progenitor response and cellular expression of the c-kit receptor. MGF and erythropoietin gave rise to macroscopic colonies and dose-dependently increased CFU-GEMM and BFU-E up to 27-fold in 15 (60%) and 20 (80%) patients, respectively. Among 17 patients with absent growth in lymphocyte-conditioned media, MGF stimulated CFU-GEMM recovery in 59%, compared to 23% with PIXY 321, 12% with IL-3 and 8% with GM-CSF. Cytokine combinations did not augment recovery of erythropoietin-dependent progenitors above that achieved with MGF alone. MGF and/or IL-3 were comparatively weak stimulants of CFU-GM formation, whereas GM-CSF and PIXY in combination with MGF increased colony number 2- to 15-fold in 60 and 70% of patients, respectively, while preserving maturation competence as evidenced by colony composition and increased colony/cluster ratio. The stimulatory effects of MGF were observed in all morphologic categories of MDS except chronic myelomonocytic leukemia. A mononuclear cell population expressing the c-kit receptor was identified by flow cytometry in 57% of cases. Neither SR-1 reactivity nor cytogenetic pattern predicted progenitor response to MGF. These data indicate that MGF improves the colony-forming capacity of hematopoietic progenitors in MDS and is a potent co-stimulant of multipotent and committed progenitor recovery. The heterogeneity in MGF responsiveness implies an intrinsic defect in growth regulation not explained by cellular loss of c-kit display.
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PMID:Mast cell growth factor (c-kit ligand) restores growth of multipotent progenitors in myelodysplastic syndrome. 751 48

We previously demonstrated that highly purified normal human blood burst-forming units-erythroid (BFU-E) need the direct action of recombinant human stem cell factor (rSCF) in the presence of recombinant human erythropoietin (rEP) and recombinant human interleukin-3 (rIL-3) for further development in a serum-free medium. To study the response of polycythaemia vera (PV) BFU-E to rSCF, we performed dose-response experiments in a serum-free medium using highly purified BFU-E from PV patients. A marked increase in the number of PV bursts occurred with increasing concentrations of rSCF, compared to normal burst formation, when the cells were cultured in the presence of rIL-3 at 1 U/ml. The percentage of maximum growth for normal BFU-E was 31 +/- 11% while for PV it was 64 +/- 9% at the highest concentration of rSCF (P < 0.01). Without rIL-3, only 11% of maximum normal BFU-E growth occurred as the rSCF concentration was increased and the size of the colonies was very small, but PV BFU-E still expressed 48% of the maximum number of large erythroid bursts (P < 0.001). This demonstrated an enhanced sensitivity of PV BFU-E to rSCF, compared to normal BFU-E. The pattern of 59Fe incorporation into haem after 8 d of cell culture indicated that PV BFU-E had a time course of maturation and a degree of cellular maturity similar to normal BFU-E. The percentage positivity and intensity of c-kit receptors on PV erythroid cells were examined using immunofluorescence flow cytometry. When BFU-E, CFU-E, or erythroblasts were incubated with phycoerythrin-conjugated SR-1 anti-c-kit receptor monoclonal antibody, 90% of the PV and normal BFU-E displayed c-kit receptor at comparable intensities, as well as 80% of the PV and normal CFU-E. A distinct loss of c-kit expression occurred with erythroid differentiation beyond the CFU-E stage, but at all stages no difference of c-kit receptor expression was evident for PV erythroid precursors compared to normal precursors. These results indicate that the hypersensitivity to rSCF did not appear to be related to the number of c-kit receptors. Since we have previously shown that highly purified PV BFU-E are hypersensitive to rIL-3 and rGM-CSF, as well as rEP, it is now evident that PV BFU-E are hypersensitive to each of the cytokines that have a prominent role in guiding their normal proliferation and differentiation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Polycythaemia vera. III. Burst-forming units-erythroid (BFU-E) response to stem cell factor and c-kit receptor expression. 751 94

We have studied the effects of recombinant human interleukin-9 (IL-9), alone and combined with stem cell factor (SCF, c-kit ligand), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) on the clonogenic proliferation of highly enriched human hematopoietic CD34+ and CD34+CD33-DR- progenitor cells. Colony assays were performed under serum-containing and serum-free conditions. IL-9, as a single agent, did not support colony formation. The addition of erythropoietin (Epo) to IL-9 induced the growth of erythroid progenitors (BFU-E) derived from both CD34+ and CD34+CD33-DR- cells. The IL-9-dependent growth of BFU-E derived from CD34+ cells was increased in an additive manner by SCF and, to a lesser extent, by IL-3, whereas CD34+CD33-DR- erythroid precursors were also responsive to GM-CSF in combination with IL-9. The addition of SCF to IL-9 did stimulate the development of CD34+ and CD34+CD33-DR- macroscopic, multicentered BFU-E and multilineage colonies (CFU-GEMM). When IL-9 was used in serum-free conditions, the growth of CD34+ and CD34+CD33-DR- BFU-E was observed in the presence of Epo. Moreover, a marked synergy on BFU-E colony formation was evident when IL-9 was combined with SCF, and their activity was enhanced by the addition of IL-3. IL-9 showed a negligible proliferative activity on colony-forming units-granulocyte/macrophage (CFU-GM). However, it increased the number of CD34+CD33-DR- CFU-GM responsive to IL-3 (37% of the colonies generated by phytohemagglutinin-stimulated lymphocyte conditioned medium [PHA-LCM]). The effects of IL-9 on CD34+CD33-DR- cells were also studied in a short-term suspension culture system, which evaluates the proliferation of progenitors earlier than day 14 CFU-C (Delta assay). In this system, IL-9 had a minimal activity on its own. In combination with SCF, however, it induced a nine-fold expansion of CD34+CD33-DR- cells, which generated a greater number of CFU-GM than BFU-E in secondary methylcellulose cultures. These experiments indicate that IL-9 induces the proliferation of very primitive human erythroid cells, and this effect is potentiated by SCF and other cytokines. Furthermore, IL-9 synergizes in vitro with the c-kit ligand in expanding the pool of early pluripotent hematopoietic progenitor cells.
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PMID:Stem cell factor (c-kit ligand) enhances the interleukin-9-dependent proliferation of human CD34+ and CD34+CD33-DR- cells. 752 Mar 94


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