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)

Previous studies have suggested that Steel factor (SF) can influence the behavior of many types of hematopoietic progenitor cells both in vivo and in vitro, although whether these may include the most primitive populations of totipotent repopulating cells remains controversial. To approach this question, we measured the number of Sca1+Lin-WGA+ cells, the number of cells with demonstrable myeloid (long-term culture-initiating cell [LTC-IC]) or both myeloid and lymphoid (LTC-IC(ML)) potential in 4- to 5-week-old long-term cultures containing irradiated primary marrow feeder layers, and the number of multilineage long-term in vivo repopulating cells (competitive repopulating unit [CRU]) present in the marrow of W42/+ or W41/W41 mice compared to +/+ controls. There was no significant effect of either of these W mutations on the number of Sca1+Lin-WGA+ cells and, in W41/W41 mice, neither LTC-IC nor LTC-IC(ML) populations appeared to be affected. On the other hand, although W41/W41 and W42/+ cells could both be detected in the in vivo CRU assay, their numbers were markedly reduced (17- and seven-fold, respectively) in spite of the fact that both of these W mutant genotypes contained near normal numbers of day-9 and -12 colony-forming units-spleen (CFU-S). In vitro quantitation of erythroid (burst-forming units-erythroid [BFU-E]), granulopoietic (CFU-granulocyte/macrophage [CFU-GM]), multilineage (CFU-granulocyte/erythrocyte/monocyte/macrophage [CFU-GEMM]), and pre-B clonogenic progenitors (CFU-pre-B) also revealed no differences in the numbers (or proliferative potential) of any of these cells when W41/W41 or W42/+ and normal mice were compared, although day 3 BFU-E from both types of W mutant mice showed no response to the typical enhancing effect exerted by SF on their +/+ counterparts. Taken together, these findings are consistent with the view that SF activation of c-kit receptor-induced signaling events is not a rate-limiting mechanism controlling red blood cell production during normal development until hematopoietic cells differentiate beyond the day-3 BFU-E stage. Nevertheless, normal hematopoietic stem cells do appear to be responsive to SF, since their W mutant counterparts display a disadvantage in the in vivo setting which is exaggerated under conditions of hematopoietic regeneration. On the other hand, alternative mechanisms also appear to contribute to the regulation of hematopoietic stem cell numbers in vivo and to their detection as LTC-IC in vitro.
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PMID:Studies of W mutant mice provide evidence for alternate mechanisms capable of activating hematopoietic stem cells. 864 40

Miniature swine are being used as a large animal model in which cultured and retrovirus-transduced hematopoietic stem cells (HSC) can be tested in a reproducible manner for their long-term in vivo repopulating ability. As part of these studies, long-term bone marrow culture (LTBMC) and progenitor colony assay systems were developed and used to characterize the in vitro growth potential and in vivo frequency of hematopoietic progenitors in this species. We found that LTBMCs initiated with a single marrow inoculum produced myeloid colony progenitors continuously for at least 7 weeks. The sites of myelopoietic activity in these cultures were uniquely restricted to isolated, morphologically diverse germinal centers rather than more disperse cobblestone patches. We also used the progenitor assay to screen several human and murine recombinant cytokines for cross-reactivity to swine bone marrow cells, including interleukin-3 (IL-3), IL-6, Il-11, granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF), c-kit ligand (also called mast cell growth factor [MGF]), and erythropoietin (Epo). With the exception of human and murine IL-3, each of the cytokines tested induced swine progenitor colony formation to varying degrees, with some combinations leading to the formation of primitive multilineage and high proliferative potential colonies. Finally, in an attempt to characterize alternative sources of HSC from swine, we compared the progenitor content of adult and juvenile swine bone marrow and fetal liver. The fetal liver samples were found to be highly enriched for both primitive and mature progenitors, while analysis of postnatal marrow samples revealed an approximately two-fold decline in overall progenitor frequency between the ages of 10 and 20 weeks. Taken together, these studies demonstrate the development and use of in vitro culture methods for characterizing hematopoietic elements from miniature swine and suggest a hierarchy of progenitor cell content in various hematopoietic tissues from the large animal model.
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PMID:Culture and characterization of hematopoietic progenitor cells from miniature swine. 869 52

We have studied the effects of recombinant human thrombopoietin (TPO; mpl ligand) on the proliferation of human primitive hematopoietic progenitors in vitro. CD34+ cells were enriched for cell-cycle-dormant primitive progenitors by separation on the basis of expression of c-kit and CD38. In the presence of varying combinations of TPO, Steel factor (SF), and interleukin-3 (IL-3), CD34+/c-kit(low)/CD38neg/low cells produced fewer colonies than CD34+/c-kit(low)/CD38high cells. However, when cultured in suspension for 7 days and replated in methylcellulose culture for measurement of colony-forming cells, the former population generated more colony-forming cells than the latter. In suspension culture of CD34+/c-kit(low)/CD38neg/low cells, TPO acted synergistically with SF and/or IL-3 in support of the production of colony-forming cells for granulocyte/macrophage colonies, erythroid colonies, and mixed colonies. Culture studies of individual CD34+/c-kit(low)/CD38neg/low cells provided the evidence for the direct nature of the effects of TPO. When combined with SF, TPO showed stronger stimulation of production of progenitors in suspension culture than other early-acting factors, such as IL-6, IL-11, and granulocyte colony-stimulating factor (G-CSF). TPO may be an important cytokine for in vitro manipulation of human hematopoietic stem cells.
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PMID:Thrombopoietin supports proliferation of human primitive hematopoietic cells in synergy with steel factor and/or interleukin-3. 869 89

The clonal growth of progenitor cells from myelodysplastic syndromes (MDS) can be subdivided into four growth patterns: (1) normal, (2) no growth or low plating efficiency, (3) low colony and high cluster number, and (4) normal or high colony number with a large number of clusters. The former two (1 and 2) can be referred to as nonleukemic patterns and latter two (3 and 4) as leukemic. In a search for a role for cytokines in leukemic-type growth of MDS progenitor cells, marrow CD34+ cells were purified up to 94% for 8 normal individuals and 88% for 12 MDS patients, using monoclonal antibodies and immunomagnetic microspheres (MDS CD34+ cells). The purified CD34+ cells were cultured for 14 days with various combinations of cytokines, including recombinant human macrophage colony-stimulating factor (rM-CSF), granulocyte-CSF (rG-CSF), granulocyte-macrophage-CSF (rGM-CSF), interleukin-3 (rIL-3), and stem cell factor (SCF; a ligand for c-kit) in serum-free medium. The clonal growth of MDS CD34+ cells supported by a combination of all of the above cytokines was subdivided into the two patterns of leukemic or nonleukemic, and then the role of individual or combined cytokines in proliferation and differentiation of MDS CD34+ cells was analyzed in each group. Evidence we obtained showed that SCF plays a central role in the leukemic-type growth of MDS CD34+ cells and that G-CSF, GM-CSF; and/or IL-3 synergize with SCF to increase undifferentiated blast cell colonies and clusters over that seen in normal CD34+ cells. SCF is present in either normal or MDS plasma at a level of nanograms per milliliter, and this physiologic concentration of SCF can stimulate progenitor cells. This means that progenitor cells are continuously exposed to stimulation by SCF in vivo and that MDS leukemic cells have a growth advantage over normal blast cells. This depends, at least in part, on cytokines such as G-CSF, GM-CSF, IL-3, and SCF.
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PMID:Role of cytokines in leukemic type growth of myelodysplastic CD34+ cells. 870 90

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is crucial to hematopoiesis, melanogenesis, and gametogeneis. Although the enzymatic activity of the c-kit product (KIT) is regulated by its ligand, both the Val559-->Gly (G559) mutation in the juxtamembrane domain and the Asp814-->Val (V814) mutation in the phosphotransferase domain lead to constitutive activation of KIT. By retroviral infection of hematopoietic progenitor cells with KIT(G559) or KIT(V814), KIT(G559) induced development of granulocyte/macrophage and mast-cell colonies in vitro without the addition of exogenous growth factors. KIT(V814) induced factor-independent growth of various types of hematopoietic progenitor cells, resulting in the development of mixed erythroid/myeloid colonies in addition to granulocyte/macrophage and mast-cell colonies. Furthermore, transplantation of KIT(G559) and KIT(V814)-infected bone marrow cells led to development of acute leukemia in one of 10 and six of 10 transplanted mice, respectively. No mice developed hematologic malignancies after transplantation of wild-type KIT-infected cells. Furthermore, transgenic mice expressing KIT(V814) developed acute leukemia or malignant lymphoma. These results demonstrate a direct role of the mutant KITs, particularly KIT(V814), in tumorigenesis of hematopoietic cells and suggest that similar mutations may contribute to the development of human hematologic malignancies.
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PMID:Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase. 870 59

Eighty six of 430 acute myeloblastic leukemia (AML) patients (20.0%) and forty of 173 acute lymphoblastic leukemia (ALL) patients (23.1%) had CD7 on their leukemia cells. CD7(+) AML occurred at a younger age than CD7(-) AML, and is more frequent in males. Hepatomegaly and central nervous system involvement were also more frequent in CD7(+) AML than in CD7(-) AML. The age of onset of CD7(+) ALL is also younger than that of CD7(-) ALL. Phenotypically, CD(+) AML expressed CD34, HLA-DR, and TdT more frequently than CD7(-) AML while CD7(+) ALL expressed CD13/33 more often than CD7(-) ALL cells responded most significantly to interleukin 3 (IL-3), whereas most CD7(-) AML cells responded more significantly to granulocyte macrophage-colony stimulating factor (GM-CSF) and/or granulocyte (G)-CSF than to IL-3. CD7(+)sCD3(-)CD4(-)CD8(-) ALL expressed G-CSF receptor and c-kit mRNA more frequently, which is not usual in other types of ALL. P-glycoprotein (P-gp)/multi-drug resistance gene (MDR1), thought to be expressed in hematopoietic stem cells, is expressed in CD7(+) AML and CD7(+)sCD3(-) CD4(-)CD8(-) ALL significantly more often than in CD7(-) acute leukemias and the CR rate and overall survival of CD7(+)AML was worse than CD7(-) AML. These data, collectively, suggest the close association of CD7(+) AML and CD7(+)sCD3(-)CD4(-)CD8(-) ALL, not only the common expression of CD7 itself but also because their phenotypical immaturity, cytokine receptor expression, P-gp/MDR1 expression and clinical manifestations including the frequent occurrence in males and the poor prognosis. We propose that CD7(+) acute leukemia is an hematopoietic stem cell leukemia which may be separate entity.
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PMID:Biological characteristics of CD7(+) acute leukemia. 872 5

After immunizing mice with a human megakaryoblastic leukemia cell line, M-MOK, we obtained two monoclonal antibodies which recognize the human c-kit receptor. The monoclonal antibodies, designated MTK1 and MTK2, were found to specifically recognize Balb/3T3 cells transfected with human c-kit cDNA and not parent Balb/3T3 cells while showing different immunological, biochemical and biological behaviors. Both allowed visualization of the 140 kDa c-kit protein by Western blot analysis, but MTK1 detected only positive band with non-reducing conditions for sodium dodecyl sulfate-polyacrylamide gel electrophoresis. MTK1 partially inhibited the stem cell factor (SCF) induced proliferation of M-MOK cells, whereas, MTK2 was without effect. MTK1 also inhibited the bone marrow derived colony forming unit granulocyte/macrophage (CFU-GM) formed by granulocyte-macrophage colony stimulating factor (GM-CSF) and SCF. Not only anti-CD34 antibodies (HPCA-1) but also MTK1 could be shown to concentrate bone marrow CFU-GM and burst forming unit erythroid (BFU-E) effectively. The presently described monoclonal antibodies may therefore be useful for functional analysis of the ligand binding domain of the human c-kit receptor, as well as for further classification of hematopoietic stem cells in addition to the CD34 positive cells.
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PMID:Isolation and characterization of two monoclonal antibodies that recognize different epitopes of the human c-kit receptor. 872

Mast cells and blood basophils are distinct hemopoietic cells. They can be distinguished from each other and from all other lymphohemopoietic cells using antibodies against surface receptors or stored cytoplasmic molecules. In patients with myelodysplastic syndromes (MDS) or myeloproliferative syndromes (MPS), an elevation of metachromatically granulated cells (MCS) is frequently seen. These cells can be classified as basophils or mast cells using monoclonal antibodies (mAbs) against leukocyte antigens, including mast cell tryptase, c-kit (= mast cell growth factor [MGF] receptor), interleukin-3 receptor alpha chain (IL-3R alpha = CD123), and CD11b (C3biR). In a stable phase of MDS or MPS, the circulating MCS usually are basophils (histamine+, tryptase-, c-kit-, IL-3R alpha +, CD11b+). In an accelerated or terminal phase of disease, however, mast cell lineage involvement and circulating mast cell precursors (histamine+, tryptase+, c-kit+, IL-3R alpha-, CD11b-) are found in a subset of patients. The use of mAbs against mast cell antigens and granulocyte antigens is diagnostic in these patients.
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PMID:Mast cell-lineage versus basophil lineage involvement in myeloproliferative and myelodysplastic syndromes: diagnostic role of cell-immunophenotyping. 881 68

The expression and production of c-kit and its ligand, stem cell factor (SCF), in cord blood and neonates were studied. Serum SCF levels were significantly higher in cord blood, neonates aged 1-30 d, and in 4-month-old infants than in the maternal serum (P < 0.01). SCF levels decreased in children from 7 months to 15 years of age (P < 0.01). The serum soluble c-kit levels were significantly higher in cord (P < 0.01) and neonatal blood (P < 0.05) than in the maternal blood. SCF and c-kit levels in placental tissue homogenates and the culture media of decidual cells and trophoblasts were low. To determine the sites of high SCF and c-kit production in cord blood and in early neonates. SCF and c-kit mRNA expression was analysed in various tissues by polymerase chain reaction. High SCF mRNA expression was observed in human umbilical vein endothelial cells (HUVEC). Moderate c-kit mRNA expression was detected in HUVEC, the bone marrow, and cord blood. These findings suggest that endothelial cells mainly produce the SCF in cord blood and in early neonates. To confirm the role of endothelial cells in haemopoiesis, colony-forming assays were performed in the presence of HUVEC culture media, which induced the formation of high numbers of granulocyte and erythroid colonies in cord blood. IL-3, IL-6 and SCF levels were elevated in the media. Our findings suggest that endothelial cells have an important role in the maintenance and proliferation of progenitor cells in neonatal blood via the interaction of c-kit and SCF with other factors. The ex vivo expansion of cord progenitor cells in the presence of endothelial cells needs to be investigated further.
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PMID:Umbilical vein endothelial cells are an important source of c-kit and stem cell factor which regulate the proliferation of haemopoietic progenitor cells. 882 81

Aqueous extracts prepared from the murine kidney (MKE) promoted colony formation derived from murine hematopoietic progenitor cells in serum-free cultures stimulated by interleukin-3 (IL-3) and erythropoietin (Epo). MKE itself did not stimulate any colony formation. MKE preferentially enhanced granulocyte-macrophage colony forming units (CFU-GM), but did not promote any erythroid colony formation. The CFU-GM colony promotion by MKE was observed at day 6 after the culture started, and the colony-promoting activity (CPA) was maintained at the same level until day 16. MKE showed no CPA in the cultures using cells obtained from 5-FU-injected mice and from c-kit(+)-enriched treatment. Furthermore, MKE acted synergistically with granulocyte-colony-stimulating factor (CSF), macrophage-CSF, IL-6 and IL-11 on colony formation, but did not act with GM-CSF, stem cell factor and Epo. From the results of various experiments and gel-filtration chromatography, it is estimated that the colony-promoting factor detected in MKE is a heat stable protein with about 20 KDa molecular weight. These results suggest that MKE promotes colony formation by murine myeloid progenitor cells, and that the target cell populations of MKE are relatively mature in the hematopoietic differentiation pathway.
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PMID:[Biological properties of the colony-promoting activity in extracts prepared from murine kidney]. 885 17


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