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

c-kit protooncogene encodes a type III transmembrane receptor kinase, the stem cell factor receptor, or KIT. The ligand of the KIT. stem cell factor, is a cytokine that stimulates mast cell growth and differentiation. We have studied immunohistochemically KIT expression in 23 canine mast cell tumors (MCTs), 10 histiocytomas, 5 malignant melanomas, and in 2 cell lines derived from mast cells (HMC-1, human and C2, canine). As expected, KIT was detected both in the human mast cell leukemia cell line (HMC- ) and in the canine mastocytoma cell line C2. In normal canine skin, KIT expression was confined to mast cells. All canine MCTs expressed KIT, although the intensity of the staining reaction varied considerably among the 23 neoplasms. Grade III tumors showed the highest expression of KIT, whereas grade I tumors showed the lowest expression of KIT. Two patterns of KIT expression were detected in mast cells. In normal canine mast cells and in some neoplastic mast cells, KIT appeared mainly on the cell membrane. However, in many canine MCTs, KIT is accumulated in the cytoplasm, usually near the cell nucleus. The meaning of these two patterns is not clear. Expression of KIT could not be detected immunohistochemically in any of the other neoplasias investigated. According to our results, it can be concluded that most, if not all, canine MCT express KIT. Furthermore, there is an inverse correlation between the degree of differentiation and the expression of KIT. Moreover, according to our results, KIT can be used as a reliable immunohistochemical marker for canine mast cells and undifferentiated mast cell tumors.
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PMID:Canine mast cell tumors express stem cell factor receptor. 1069 17

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.
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PMID:Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. 1091 Sep 6

Patients with systemic mast cell (MC) disease, but not those with cutaneous mastocytosis, are at a high risk (10-30%) to develop life-threatening myelogenous malignancies. In a significant proportion of cases, myeloid leukemias occur. Using conventional criteria, such leukemias resemble acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or myelomonocytic leukemia (CMML). Mast cell leukemia (MCL) may also occur. Myeloid leukemias (AML, CML, CMML) can develop in indolent or aggressive mastocytosis (skin lesions present or absent) with a variable prephase of MC disease. By contrast, MCL (typically without skin lesions) often develops on a "de novo" basis, and, if at all recognized, a prephase resembling (malignant) mastocytosis, is short. MCL differs from myeloid leukemias (AML, CML, CMML) by morphologic and phenotypic cellular characteristics. In fact, MCL are strongly tryptase-positive, c-kit-positive, myeloperoxidase (MPO) -negative neoplasms with variable metachromasia and chloroacetate esterase expression, whereas an MPO-positive, tryptase-negative phenotype supports the diagnosis of a myeloid non-MC lineage disease. Thus, MCL, but also myeloid non-MC lineage leukemias can develop in patients with (systemic) mastocytosis. Little is known, however, about the pathophysiologic basis of co-evolution. In the present article, the concomitant occurrence of mastocytosis and leukemia is discussed in the light of the literature and of concepts proposed to explain the biologic basis of this phenomenon.
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PMID:Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. 1104 8

Synaptotagmin I (STG I) is a Ca(2+) sensor and one of the synaptic vesicle proteins that mediate exocytosis. To determine the mechanism of release of large granules from mast cells, we studied by immunohistochemistry the presence of STG I in mast cells in normal human tissues simultaneously with the mast cell markers mast cell tryptase (tryptase) and c-kit. The tumor cells of systemic mast cell disease (SMCD) and a human mast cell leukemia cell line (HMC-1) were also examined. Human mast cells in normal tissues and the tumor cells of SMCD expressed STG I as well as mast cell tryptase (tryptase) and c-kit. STG I mRNA and its products in HMC-1 were examined by RT-PCR analysis and immunocytochemistry, respectively. STG I expression in HMC-1 cells was compared with that in cells stimulated and non-stimulated by phorbol 12-myristate 13-acetate and also with that in NB-1 and PC12 cells, known to express STG I. STG I mRNA was detected in both non-stimulated and stimulated HMC-1 cells and in NB-1 and PC12 cells. STG I immunoreactivity was weaker than NB-1 or PC12 immunoreactivity. However, it increased in the stimulated HMC-1 cells. Mast cells expressed STG I in various states. STG I may mediate exocytosis of large granules in mast cells.
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PMID:Synaptotagmin I expression in mast cells of normal human tissues, systemic mast cell disease, and a human mast cell leukemia cell line. 1118 37

In 58 patients with mast cell disease (MCD) and three with basophilic leukemia, bone marrow (54 cases) or skin tissue (four cases) was studied immunohistochemically for expression of Kit (c-kit protein), the different isomers of transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), and their respective receptors. Kit was expressed in all cases of MCD but in none of basophilic leukemia. Expression pattern of cytokines and their receptors was variable in systemic MCD with (SMCD-HD) or without (SMCD) associated hematologic disorder. However, type I TGF-beta receptor (TGFbeta1R) was not expressed in 30% of SMCD-HD patients or in patients with mast cell leukemia, but the remaining cases of MCD showed near uniform expression. The associated hematologic disorders in TGFbeta1R-negative cases of SMCD-HD were prognostically less favorable than those associated with TGFbeta1R-positive cases of SMCD-HD. The results confirm the diagnostic value of Kit immunohistochemistry in MCD and suggest a biologically relevant heterogeneity in TGFbeta1R expression among patients with SMCD-HD.
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PMID:Immunohistochemical studies of c-kit, transforming growth factor-beta, and basic fibroblast growth factor in mast cell disease. 1173 6

A novel subtype of myeloid leukemia exhibiting a partial differentiation of mast cell-lineage cells is described. The disease is characterized by an increase in myeloblasts as well as an increase in immature (blast-like) metachromatic cells (>10% in bone marrow or blood smears). Metachromatic cells express KIT (CD117) and tryptase, but lack basophil-related antigens. In contrast to mast cell leukemia/systemic mastocytosis, metachromatic cells do not express CD2 or CD25, do not form multifocal dense aggregates in the bone marrow, and do not exhibit transforming mutations at codon 816 of c-kit. In the few patients recorded so far, a complex karyotype without recurring anomaly was found. The prognosis appears to be grave, although complete remission in response to chemotherapy has been described.
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PMID:Myelomastocytic leukemia: myeloid neoplasm characterized by partial differentiation of mast cell-lineage cells. 1203 70

Mastocytosis comprises a heterogeneous group of hematological disorders which are morphologically defined by proliferation and accumulation of tissue mast cells in one or more organs. Clinical manifestations of mastocytosis range from disseminated maculopapular skin lesions (= urticaria pigmentosa [UP]) that may spontaneously regress to highly aggressive neoplasms like mast cell leukemia or mast cell sarcoma. Recently, it could be shown that systemic mastocytosis (SM) is a clonal disorder often exhibiting mutations of c-kit, a protooncogene encoding the tyrosine kinase receptor for stem cell factor (SCF). Mutations of c-kit are considered to play a key role in the pathogenesis of mastocytosis. Therefore, we investigated the unique case of a 36 year-old male patient with indolent systemic mastocytosis (ISM) evolving from UP (cutaneous mastocytosis) by means of histology, immunophenotyping and molecular biology. At the time of initial diagnosis the bone marrow showed only a mild diffuse increase in mast cells but compact infiltrates were missing. The serum tryptase levels were normal. Five years later, however, the bone marrow histology displayed patchycompact mast cell infiltrates, which now allowed to establish the diagnosis of an ISM. The serum tryptase levels at this time were markedly elevated. At both time points, mast cells were analyzed by immunohistochemistry using anti-tryptase antibody AA1, by flow cytometry using antibodies against CD2 and CD25, and nested polymerase chain reaction (PCR) on laser-microdissected, single pooled mast cells. Immunohistochemistry revealed strong tryptase-positivity of mast cells in both cutaneous and bone marrow infiltrates. Flow cytometry yielded an aberrant expression of CD2 and CD25 on bone marrow mast cells. However, repeated thorough PCR analysis failed to unveil c-kit mutation in atypical mast cells of skin and bone marrow samples of both dates. These findings clearly show that ISM can evolve from UP. Moreover, our study provides further evidence that the c-kit mutation Asp-816-Val is not invariably present in ISM.
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PMID:Evolution of urticaria pigmentosa into indolent systemic mastocytosis: abnormal immunophenotype of mast cells without evidence of c-kit mutation ASP-816-VAL. 1268 51

Mastocytosis is a rare disease characterized by an abnormal increase of mast cells in tissues. We report a case of acute myeloid leukemia (AML) with t(8;21) and mast cell leukemia (MCL) in which the mastocytosis persisted after standard chemotherapy and allogeneic stem cell transplantation, although the myeloid leukemia achieved molecular complete remission soon after induction chemotherapy. Donor-type mast cells were noted on d31 after transplant. No c-kit mutation was found before or after the transplant. This represents the first reported case in which rapid engraftment of mast cells of donor origin was documented. Thus, the possibility that the mast cell originates from a common myeloid precursor cell may be questioned and a reactive process should be considered in some cases of systemic mastocytosis.
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PMID:Rapid engraftment of mast cells of donor origin in a case of acute myeloid leukemia with mast cell leukemia after allogeneic stem cell transplantation. 1281 87

Mutations in the proto-oncogene c-kit cause constitutive kinase activity of its product, KIT protein, and are associated with human mastocytosis and gastrointestinal stromal tumors (GISTs). Although currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinoid ansamycin antibiotic, which binds to heat shock protein 90 (hsp90) causes destabilization of various hsp90-dependent kinases important in oncogenesis. Treatment with 17-AAG of the mast cell line HMC-1.2, harboring the Asp816Val and Val560Gly KIT mutations, and the cell line HMC-1.1, harboring a single Val560Gly mutation, causes both the level and activity of KIT and downstream signaling molecules AKT and STAT3 to be down-regulated following drug exposure. These data were validated using Cos-7 cells transfected with wild-type and mutated KIT. 17-AAG promotes cell death of both HMC mast cell lines. In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction. These data provide compelling evidence that 17-AAG may be effective in the treatment of c-kit-related diseases including mastocytosis, GISTs, mast cell leukemia, subtypes of acute myelogenous leukemia, and testicular cancer.
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PMID:17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. 1455 Nov 38

Mastocytosis comprises a heterogeneous group of disorders characterized by proliferation and accumulation of mast cells in 1 or more organ systems. Mast cell leukemia (MCL) is an extremely rare subtype of mastocytosis in which a leukemic spread of mast cells and a rapid progression of disease is seen. In typical cases, mast cells are found in the peripheral blood. However, an aleukemic variant of MCL (formerly termed malignant mastocytosis) has also been described. We here report a case of aleukemic MCL with abnormal immunophenotype of mast cells and the classical c-kit point mutation Asp-816-Val (=D816V). The 75-year-old male patient had a short history of weight loss and lymphadenopathy. There were no urticaria pigmentosa-like skin lesions. The bone marrow was diffusely infiltrated with atypical mast cells that comprised more than 80% of all nucleated cells on a bone marrow smears. As assessed by immunohistochemistry, neoplastic mast cells expressed tryptase, chymase, CD2, CD25, CD68, and the KIT protein (CD117). Mutation analysis revealed the c-kit mutation D816V. Since circulating mast cells could not be detected in the peripheral blood, the diagnosis of aleukemic MCL was established in accordance to the updated WHO consensus classification. This case further supports the notion that the pathogenesis (c-kit mutation D816V) in MCL is closely related to that found in indolent mast cell disorders. However, additional (but yet unknown) molecular (genetic) defects have to be considered to explain the extremely heterogenous clinical course in these patients.
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PMID:Aleukemic mast cell leukemia with abnormal immunophenotype and c-kit mutation D816V. 1551 20


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