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)

The case of a 62-year-old man who presented with acute abdominal pain and a widespread tumor involving the retroperitoneum is described. Three weeks after initial presentation, the patient died suddenly of acute cardiac failure with signs of arrhythmia. Autopsy revealed a disseminated tumor with infiltration of the retroperitoneal fat, as well as nodules in the left testis and the right atrium. The tumor cells were reactive for CD45, vimentin, and chloroacetate esterase, but were unreactive with a broad spectrum of antibodies against myelomonocytic and lymphocytic antigens and with antibodies against tryptase and c-kit (CD117), which are characteristic markers for mast cells. However, the bone marrow exhibited the typical picture of mastocytosis, with disseminated clusters of differentiated spindle-shaped cells that stained strongly for tryptase, c-kit, and chloroacetate esterase. No infiltrates of well-differentiated mastocytosis could be detected in any of the extramedullary tissues investigated. A diagnosis of bone marrow mastocytosis with an associated undifferentiated extramedullary tumor of hemopoietic origin was established. By definition, the extramedullary tumor could not be diagnosed as a granulocytic sarcoma or (differentiated) mastocytoma, but the possibility that a mast cell progenitor could be involved in the evolution of both tumors cannot be ruled out.
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PMID:Bone marrow mastocytosis associated with an undifferentiated extramedullary tumor of hemopoietic origin. 914 Mar 15

Mastocytosis are a group of diseases characterized by abnormal proliferation of mast cells. Various forms are observed in respect to the organ system involving, clinical manifestations, and association with hematological disorders. The c-kit proto-oncogene encodes for a receptor tyrosine kinase, which plays a crucial role in hematopoiesis, especially in mast cell growth and differentiation. Mutations in the tyrosine kinase domain of c-kit have been reported in murine and human malignant cell lines, and more recently in some cases of human mast cell diseases. The biochemical and clinical aspects of these mutations are reviewed with special emphasis on the experiments which demonstrate their role in oncogenesis and mast cell proliferation.
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PMID:C-kit mutations and mast cell disorders. A model of activating mutations of growth factor receptors. 916 10

Human skin xenografted to mice with severe combined immunodeficiency syndrome (SCID) was evaluated to determine the integrity and fate of human dermal mast cells. There was an approximately 3-fold increase in number of dermal mast cells by 3 mo after engraftment (p < 0.05). These cells were responsive to conventional mast cell secretagogues and were confirmed to be of human origin by ultrastructural characterization of granule substructure and by reactivity for the human mast cell proteinase, chymase. CD1a+ Langerhans cells, also bone marrow-derived cells, failed to show evidence of concomitant hyperplasia, and increased mast cell number was not associated with alterations in number of dermal vascular profiles identified immunohistochemically for human CD31. RT-PCR analysis demonstrated human but not murine stem cell factor (SCF; also termed mast cell growth factor, c-kit ligand) mRNA in xenografts. Epidermal reactivity for stem cell factor protein shifted from a cytoplasmic pattern to an intercellular pattern by 3 mo after engraftment, suggesting a secretory phenotype, as previously documented for human cutaneous mastocytosis. The majority (>90%) of mast cells demonstrated membrane reactivity for human SCF at the time points of peak hyperplasia. These data establish SCID mouse recipients of human skin xenografts as a potential in vivo model for cutaneous mast cell hyperplasia.
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PMID:Human skin/SCID mouse chimeras as an in vivo model for human cutaneous mast cell hyperplasia. 920 63

Because in humans mast cells and basophils tend to possess nonsegmented and segmented/multi-lobular nuclei, respectively, nuclear morphology has been a major criterion for assessing the lineage of metachromatic cells of hematopoietic origin. Immature metachromatic cells with mono- and multi-lobular nuclei were both obtained when bone marrow cells from BALB/c mice were cultured for 3 weeks in the presence of interleukin-3. Analogous to the indigenous mature mast cells that reside in the peritoneal cavity and skin, both populations of in vitro-derived cells expressed the surface receptor c-kit, the chymase mouse mast cell protease (mMCP) 5, the tryptase mMCP-6, and the exopeptidase carboxypeptidase A (mMC-CPA). Immunogold electron microscopy confirmed the granule location of mMC-CPA and mMCP-6 in both populations of cells, and cytochemical analysis confirmed the presence of chymotryptic enzymes in the granules. Because mature mast cells possessing multi-lobular nuclei also were occasionally found in the skeletal muscle and jejunum of the BALB/c mouse, the V3 mouse mast cell line was used to investigate the developmental relationship of mast cells that have very different nuclear structures. After the adoptive transfer of V3 mast cells into BALB/c mice, v-abl-immortalized mast cells with mono- and multi-lobular nuclei were detected in the lymph nodes and other tissues of the mastocytosis mice that expressed c-kit, mMCP-5, mMCP-6, and mMC-CPA. These studies indicate that mouse mast cells can exhibit varied nuclear profiles. Moreover, the nuclear morphology of this cell type gives no insight as to its protease phenotype or stage of development.
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PMID:Mouse mast cells that possess segmented/multi-lobular nuclei. 920 74

The case of a 63-year-old man with a widespread retroperitoneal tumor and two tumor nodules in the left testis is described. Histopathological and cytopathological examination of tissue from the retroperitoneal tumor led to a diagnosis of lymphoreticular neoplasia. The patient died in acute cardiac failure, five weeks after initial presentation. Autopsy revealed another tumor nodule in the right atrium. Macroscopically, the bone marrow appeared normal. The tumor cells were reactive for CD45, vimentin and chloroacetate esterase, but were uncreative with a broad spectrum of antibodies against myelomonocytic and lymphocytic antigens and antibodies against tryptase and c-kit (CD117), characteristic markers for mast cells. However, the bone marrow exhibited the typical picture of mastocytosis. A diagnosis of bone marrow mastocytosis with an associated secondary extramedullary mast cell sarcoma was established. The cause of death was heart failure due to arrhythmia caused by an exophytic atrioseptal tumor nodule.
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PMID:[Association of bone marrow mastocytosis with extremely immature extramedullary mast cell sarcoma]. 927 45

Murine studies have demonstrated that, as with other nematodes, infection with the intestinal nematode Trichinella spiralis is associated with a pronounced intestinal mastocytosis, eosinophilia and an elevation in serum levels of total IgE. Both interleukin (IL)-4 and IL-5 are clearly important in the generation of IgE responses and eosinophilia, respectively, but the control of mucosal mastocytosis in vivo is not as well defined. Mucosal mast cells appear to be particularly important with regard to T. spiralis infections as there is good evidence to suggest their involvement in expulsion of the parasite from the host. In this study we examined the effect of the overproduction of the Th2 cytokine IL-9 on infection with this nematode. We demonstrate that naive IL-9-transgenic mice have an intense intestinal mastocytosis and high serum levels of mouse mast cell protease-1. Moreover, upon infection high titers of parasite-specific IgG1 were observed with a heightened mast cell response, which was associated with the rapid expulsion of T. spiralis from the gut. Furthermore, as depression of this mast cell response, using anti-c-kit antibodies, resulted in the inability of these mice to expel the parasite, this study clearly demonstrates an activity of IL-9 on mucosal mastocytosis and the host protective immune response in vivo.
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PMID:Interleukin-9 is involved in host protective immunity to intestinal nematode infection. 936 7

Mast cells and basophils express certain remarkable similarities in mediator content, histochemical characteristics, and function. Yet a large body of evidence now indicates that the mast cell and basophil lineages are distinct. Stem cell factor, the ligand for the receptor encoded by c-kit, is a major growth factor for mast cells in both rodent and primate species, and can modulate mast cell secretory function. Moreover, abnormalities affecting the stem cell factor receptor or stem cell factor might contribute to some cases of mastocytosis or mast cell neoplasms. By contrast, basophils can develop independently of stem cell factor, and are not as sensitive as mast cells to the effects of stem cell factor on mediator secretion. In addition, the cytokine interleukin-3 greatly augments the production of human basophils, but has little or no growth promoting activity for human mast cells.
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PMID:Mast cell and basophil development. 937 Dec 57

The stem cell factor (SCF)c-kit receptor interaction plays a critical role in the development and survival of mast cells. Several studies have also associated c-kit receptor mutations with the human diseases, mastocytosis and piebaldism. Overexpression of c-kit has been reported to be associated with myeloproliferative disorders and myelodysplastic syndromes. Using peripheral blood mononuclear cells (PBMCs) from 11 patients with indolent mastocytosis (category I), mastocytosis with an associated hematologic disorder (category II), or aggressive mastocytosis (category III); a patient with CMML unassociated with mastocytosis, and PBMCs from 13 normal subjects, we examined the level of expression of c-kit mRNA along with other c-kit isoforms to determine if overexpression of the c-kit receptor was associated with mastocytosis. Using quantitative competitive PCR, c-kit mRNA levels on average were found to be statistically elevated in the five patients with mastocytosis with an associated hematologic disorder and in the patient with aggressive mastocytosis as compared with controls, but not elevated in patients with indolent mastocytosis. The relative mRNA expression for the two c-kit isoforms was not significantly different in the mastocytosis patients compared with controls. This demonstration of the overexpression of c-kit mRNA in mastocytosis, and particularly those patients with clinical evidence of myelodysplastic syndrome, adds evidence to support the conclusion that mastocytosis, at least in some patients, is a feature of myelodysplasia; and suggests that determination of c-kit mRNA expression in PBMCs may provide an additional approach to assessing prognosis.
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PMID:Elevated expression of the proto-oncogene c-kit in patients with mastocytosis. 951 79

Myelodysplastic syndromes (MDS) may be accompanied by systemic mastocytosis. The mechanisms which play a role in the evolution of mastocytosis, however, are not well understood. We report on a case of refractory and anemia with ringed sideroblasts (RARS), and co-existing bone marrow mastocytosis. Compact mast cell (MC) infiltrates were detected in bone marrow sections by immunohistochemistry using an antibody to tryptase. In addition, the MC were found to express c-kit, the tyrosine kinase receptor for MGF (mast cell growth factor = stem cell factor, SCF). Activating point mutations in the kinase domain of c-kit (often found in mastocytosis) were not detectable. However, the mononuclear cells (MNC) of the bone marrow expressed mRNA specific for MITF, a transcription factor that regulates expression of c-kit and differentiation of MC. Surprisingly, the c-kit ligand SCF was found to augment expression of MITF mRNA in bone marrow MNC. Whether this augmentation represents a general response (preventing loss of growth factor receptor expression during cell maturation) common to all types of hemopoietic progenitors, or is confined to (some forms of) mastocytosis, remains unknown.
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PMID:Detection of mi transcription factor (MITF) mRNA in a case of myelodysplastic syndrome and bone marrow mastocytosis. 955 2

IL-9 transgenic mice were analyzed for the presence of mast cells in different tissues. In these mice, increased mast cell infiltration was found in the gastric and intestinal epithelium as well as in the upper airways and kidney epithelium, but not in other organs, such as skin. IL-9 transgenic mast cells do not show signs of massive degranulation such as that found in IL-4 transgenic mice and are not involved in spontaneous pathologic changes. Gastric mast cells showed a phenotype related to connective-type mast cells, since they were stained by safranin, and strong expression of mouse mast cell protease-4 and -5 was found in this organ. However, they also expressed proteases related to the mucosal cell type, such as mouse mast cell protease-1 and -2. In vitro, although IL-9 by itself did not induce mast cell development from bone marrow progenitors, it strongly synergized with stem cell factor for the growth and differentiation of mast cells expressing the same protease pattern as that observed in IL-9 transgenic mice. Since constitutive stem cell factor expression was observed in vivo, and anti-c-Kit Abs inhibited IL-9 transgenic mastocytosis in the gut, this synergistic combination of factors is likely to be responsible for the mastocytosis observed in IL-9 transgenic mice. Taken together, these data demonstrate that IL-9 induces the in vivo amplification of a nonclassical mast cell subset with a mucosal localization but expressing proteases characteristic of both connective tissue-type and mucosal mast cells.
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PMID:Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice. 955 7


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