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)

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

The GM/SO cell line bears a high level of stem cell factor receptors (SCF-R) i.e. c-kit protein, and therefore constitutes a potential model for studying the regulation of this crucial receptor on myeloid cells. In this study we evaluated the effect of tumor necrosis factor alpha (TNF-alpha) on the expression of SCF-R by flow cytometry. In contrast to 1 hour of preincubation, the experiments carried out after 24 hours preincubation revealed that TNF-alpha, if added alone, reduced the density of SCF-R on GM/SO cells in a dose-dependent manner. However, if combined with GM-CSF, which per se downregulates the SCF-R on these cells as well, TNF-alpha antagonized the effect of GM-CSF and slightly increased the density of SCF-R. Yet the cells incubated for 24 hours in medium without cytokines invariably expressed a higher level of SCF-R than the cells incubated in the presence of TNF-alpha and GM-CSF, either alone or in combination. In contrast to these cytokines, stem cell factor (SCF), which was also tested simultaneously in all experiments, downregulated its own natural receptor on these cells also after a preincubation of 1 hour. Furthermore, prolonged exposure of GM/SO cells to TNF-alpha for 5-7 days yielded a monocyte-macrophage-like morphology of some cells as these cells displayed an apparent glass and plastic adherence. In contrast, no such morphological changes could be observed in the presence of GM-CSF or SCF.
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PMID:Regulation of the density of the stem cell factor receptor (c-kit) by tumor necrosis factor alpha on a human myeloid cell line. 751 54

The effects of recombinant canine granulocyte colony-stimulating factor (rcG-CSF) and recombinant canine stem cell factor (rcSCF), a c-kit ligand, on the circulation of hematopoietic progenitor and stem cells were studied in a canine model. Administration of rcG-CSF (10 micrograms/kg) for 7 days led to a 5.4-fold increase in CFU-GM/mL of blood, while 7 days of rcSCF (200 micrograms/kg) led to an 8.2-fold increase. Although treatment with low-dose rcSCF (25 micrograms/kg) had no effect on the level of peripheral blood progenitors, 7-day exposure to a combination of G-CSF plus low dose SCF led to a 21.6-fold increase (P = .03). To assess the ability of these factors to increase the circulation of cells capable of rescuing animals after lethal total body irradiation (TBI), 1 x 10(8) peripheral blood mononuclear cells (PBMC)/kg were collected and cryopreserved from animals after 7 days of treatment with G-CSF, SCF or a combination of the two. One month later, animals were exposed to 9.2 Gy TBI and transplanted with the previously collected cells. Control animals transplanted with 1 x 10(8) PBMC/kg collected without pretreatment died with marrow aplasia 11 to 29 days after TBI as did animals treated with only low-dose SCF before cell collection. In contrast, all animals given PBMC collected after G-CSF, high-dose SCF, or a combination of G-CSF plus low-dose SCF recovered granulocyte function. Recovery to 500 granulocytes/microL after transplant took 17, 18.8, and 13.6 days, respectively, (P = .056 for the difference between the combination G-CSF-SCF group and the other two groups). In both the G-CSF and SCF groups, 4 of 5 animals completely recovered while 1 of 5 in each group died with prolonged thrombocytopenia. In the combination group, all 5 animals became long-term survivors. These studies demonstrate that both G-CSF and SCF dramatically increase the level of peripheral blood hematopoietic progenitor and stem cells and support the view that these factors can act synergistically.
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PMID:Effects of granulocyte colony-stimulating factor and stem cell factor, alone and in combination, on the mobilization of peripheral blood cells that engraft lethally irradiated dogs. 751 22

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

Stem cell factor (SCF), a key regulator of hematopoiesis, potently synergizes with a number of hematopoietic growth factors. However, little is known about growth factors capable of inhibiting the actions of SCF. TNF-alpha has been shown to act as a bidirectional regulator of myeloid cell proliferation and differentiation. This study was designed to examine interactions between TNF-alpha and SCF. Here, we demonstrate that TNF-alpha potently and directly inhibits SCF-stimulated proliferation of CD34+ hematopoietic progenitor cells. Furthermore, TNF-alpha blocked all colony formation stimulated by SCF in combination with granulocyte colony-stimulating factor (CSF) or CSF-1. The synergistic effect of SCF observed in combination with GM-CSF or IL-3 was also inhibited by TNF-alpha, resulting in colony numbers similar to those obtained in the absence of SCF. These effects of TNF-alpha were mediated through the p55 TNF receptor, whereas little or no inhibition was signaled through the p75 TNF receptor. Finally, TNF-alpha downregulated c-kit cell-surface expression on CD34+ bone marrow cells, and this was predominantly a p55 TNF receptor-mediated event as well.
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PMID:Tumor necrosis factor-alpha inhibits stem cell factor-induced proliferation of human bone marrow progenitor cells in vitro. Role of p55 and p75 tumor necrosis factor receptors. 751 28

In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulator in vitro. In these studies, we examined the in vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100 micrograms/kg/day), rmGM-CSF (100 micrograms/kg/day), rmIL-3 (100 micrograms/kg/day), or combinations of these cytokines on days 1-17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 either produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results of in vitro studies evaluating the effects of these cytokines on induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size. These studies demonstrate a dichotomy between MGF-induced effects in vivo and in vitro and emphasize that caution should be taken in attempting to predict cytokine interactions in vivo in hemopoietically injured animals based on in vitro cytokine effects.
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PMID:Mast cell growth factor (C-kit ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3: in vivo hemopoietic effects in irradiated mice compared to in vitro effects. 752 Jul 25

We assessed the expression of the adhesion molecules leukocyte function antigen-1 (LFA-1, CD11a), intercellular adhesion molecule-1 (ICAM-1, CD54), homing-associated cell adhesion molecule (H-CAM, CD44), and c-kit (stem cell factor receptor) on the CD34+ progenitor population from the leukapheresis products of 23 patients (LP CD34+). For blood stem cell collection granulocyte colony-stimulating factor (G-CSF) or interleukin-3/granulocyte-macrophage colony-stimulating factor (IL-3/GM-CSF) was administered after cytotoxic chemotherapy. Furthermore, bone marrow- and blood-derived CD34+ progenitor cells from 6 normal volunteers (BM and PB CD34+) were analyzed. LFA-1 expression was higher on PB CD34+ (88.2 +/- 2.5%, mean +/- SEM) than on BM CD34+ (75.3 +/- 4.3%). Following cytokine administration, LFA-1 was expressed on only 59.7 +/- 3.7% of LP CD34+ at a low fluorescence intensity, suggesting that down-regulation of LFA-1 may facilitate the egress of cells from the bone marrow and prolong their circulation. In contrast, ICAM-1 was weakly positive on CD34+ cells from all sources. CD44 was expressed on the vast majority of CD34+ cells (> 95%) in all samples studied. The highest proportion of CD34+ cells costaining for c-kit was found in normal bone marrow (32.2 +/- 3.3%). In normal peripheral blood and after cytokine mobilization, fewer of the CD34+ cells weakly expressed c-kit (< 15%). The low percentage and level of c-kit expression may indicate that the majority of cytokine-mobilized CD34+ cells are lineage-committed progenitor cells, as reflected by the coexpression pattern for CD38, HLA-DR, and CD33.
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PMID:Expression of adhesion molecules and c-kit on CD34+ hematopoietic progenitor cells: comparison of cytokine-mobilized blood stem cells with normal bone marrow and peripheral blood. 752 8

Stem cell factor is a recently identified earliest-acting hematopoietic growth factor and a ligand for the c-kit proto-oncogen. Based on our recent observations that recombinant rat interleukin-3 (IL3), human interleukin-6 (IL6) and murine granulocyte-macrophage colony stimulating factor (GM-CSF) possessed different degrees of suppressive activities on the proliferation of LT 12 cell line derived from BNML rat leukemic model, SCF was evaluated alone and in combination with either IL3, IL6 or GM-CSF for effects on leukemopoiesis in vitro. The results indicated that SCF alone had suppressive effect on DNA synthesis and colony forming unit-leukemic blast (CFU-L) in LT12 cells. 100ng/ml of SCF caused substantial reduction in colony number and 3H-TdR uptake although this suppression was of lower magnitude than those induced by IL3, IL6 or GM-CSF. Enhanced suppression on the proliferation of LT12 cells was observed when SCF was used in combination with one of these three factors. Among these combinations, SCF+GM-CSF or SCF+IL6 resulted in more suppression on LT12 cells than SCF+IL3 did. Combination of SCF with two or three factors produced even more suppression. No apparent effect on the size of leukemic colony was seen. Furthermore, in growth kinetics study of LT12 cells in the presence of SCF production of LT12 cells declined. Thus, SCF appears to have divergent hematopoietic activities on BNML rat model: effective stimulation of granulopoiesis and weak suppression of leukemopoiesis.
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PMID:[Effects of recombinant stem cell factor on the proliferation in vitro of LT12 acute promyelocytic leukemic cell line]. 752 53

A study of gene expression of GM-CSF, IL-3, c-kit ligand, and IL-1 by bone marrow stromal cells of mice who were treated with an LD50 cytosine arabinoside (Ara-C) dose was carried out. It was shown previously that this dose causes extensive hematopoietic damage which is followed by regeneration in surviving mice. Using PCR, we demonstrated GM-CSF and IL-1 expression by adherent cells taken from marrow fibroblast layers following Ara-C-induced hematopoietic damage and during marrow regeneration, while expression in control layers was not detected. The IL-3 gene was not expressed either by layers of Ara-C-treated mice or by controls, probably due to the absence of T-lymphocytes in 2-4 week old cultures. The c-kit ligand gene was expressed by layers during marrow regeneration and by control layers, but was absent during the stage of hematopoietic damage. In parallel, in vitro cytokine production was evaluated. While IL-3 and GM-CSF were not present in the conditioned medium of marrow fibroblast layers either from Ara-C-treated mice or controls, IL-1 was found in low concentrations in cultures from Ara-C-treated animals. We conclude that GM-CSF, c-kit ligand and IL-1 have important roles in sustaining marrow regeneration following extensive damage. The role of IL-3 in marrow regeneration cannot be assessed in fibroblast layers of 2-4 week incubation where T-lymphocytes are generally absent.
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PMID:Cytokine and growth factor gene expression by bone marrow stroma of mice with damaged hematopoiesis and during regeneration. 752 95

Stem cell factor (CSF), also called c-kit ligand (KL) or mast cell growth factor (MGF) is a peptide growth factor/cytokine with broad activities, especially on hematopoiesis. Its physiological role is best understood through the naturally occurring steel and W mutations in the mouse. This cytokine has recently been made available because of molecular cloning and its expression in recombinant form SCF is produced by a variety of cells, especially fibroblast, and interacts with target cells in each of the hematopoietic lineages to stimulate proliferation and differentiation. It has been found that SCF is important for the survival, proliferation and differentiation of mast cells and that it influences all stages of their development. SCF activity is not restricted to hematopoiesis, as it plays an important role in the development of germ cells and melanocytes as well. Preclinical studies show that SCF can protect against lethal irradiation, elicit multilineage responses in peripheral blood and bone marrow cellularity and increase circulating peripheral blood progenitor cells in a dose-dependent manner. Recombinant human SCF has major clinical potential through its synergy with other factors, especially G-CSF, to enhance mobilization of stem cells in peripheral blood.
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PMID:[Stem cell factor]. 752 11


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