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 ability to generate dendritic cells (DCs) in sizeable numbers has enormous implications for the development of clinically-effective antigen presentation procedures for cancer immunotherapy. We evaluated the generation of immunostimulatory DCs from peripheral blood CD34+ cells collected from healthy donors. CD34+ cells purified from leukapheresis product were seeded at 1 x 10(4) cells/mL in complete medium supplemented with GM-CSF, TNF alpha, IL-4, c-kit ligand, and flt3 ligand (FL). By day 14 of culture in the presence of GM-CSF + TNF alpha, the total cell number increased by 23.4 +/- 5.4-fold compared to the starting number of CD34+ cells. When the c-kit and FL were added to GM-CSF and TNF alpha, the cell number increased by 109.8 +/- 11.2-fold without affecting the immunophenotype of recovered cells. Flow cytometric analysis indicated that cells with the markers of mature dendritic cells, i.e., CD1a +CD14 -HLA-DR+, and CD80+CD86+HLA-DR+, constituted 49.0% +/- 7.5%, and 38.9% +/- 6.5%, respectively. This pattern of expression of surface antigen was unchanged whether the c-kit ligand and/or FL was added. The irradiated CD1a+HLA-DR+ cells recovered from in vitro cultures elicit a vigorous proliferation of allogeneic peripheral blood T-cells, irrespective of cytokine combinations. These findings provide advantageous tools for the large-scale generation of DCs that are potentially usable for clinical protocols of immunotherapy or vaccination in patients undergoing cancer treatment.
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PMID:Ex vivo generation of functional dendritic cells from mobilized CD34+ hematopoietic stem cells. 975 99

An association between mediastinal germ cell tumors (MGCT) and hematological malignancies (e.g. acute leukemia, malignant histiocytosis) has been recognized since 1984. A rare case of mediastinal mature teratoma with angiosarcoma, a hematopoietic region and granulocytic sarcoma is reported in a 29-year-old male. The resected tumor was 9.0 x 6.5 cm, weighed 65 g and showed extensive necrosis, forming a cyst. The histological features of the tumor showed a mature teratoma, which contained a large gland lined by ciliated epithelium, hyalinous cartilage, a paraganglion-like structure, well-differentiated angiosarcoma with atypical hematopoiesis composed of CD34-positive cells, and malignant round cells. The malignant round cells did not stain for CD34 but were positive for leukocyte common antigen (LCA) and c-kit product. From these findings, the round cells were diagnosed as granulocytic sarcoma. The patient died of metastasis of the granulocytic sarcoma in the tonsils and cervical lymph nodes 8 months after surgery. A leukemic condition was not present throughout the clinical course. The association between MGCT and hematological malignancy is a distinctive syndrome. However, its pathogenesis is still obscure and the origin of the hematopoietic malignancy has not been fully elucidated. In this particular case, it is suggested that the granulocytic sarcoma might have arisen from the abnormal hematopoietic area in the mediastinal teratoma.
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PMID:Mediastinal mature teratoma with coexistence of angiosarcoma, granulocytic sarcoma and a hematopoietic region in the tumor: a rare case of association between hematological malignancy and mediastinal germ cell tumor. 977 15

Human rhabdomyosarcoma cells produce autocrine and paracrine growth factors that can sustain their growth and malignancy. Here we report constitutive production of stem cell factor (SCF) by 5 of 5 human rhabdomyosarcoma cell lines both of alveolar and embryonal histotype. SCF production, ranging from 30 to 162 pg/ml, was independent from the degree of myogenic differentiation and was not modulated by exogenous addition of retinoic acid (RA) or tumor necrosis factor-alpha (TNF-alpha). Four of 5 rhabdomyosarcoma cell lines expressed the mRNA for SCF receptor c-kit, while the 5th cell line became weakly positive for c-kit mRNA only after stimulation with retinoic acid. On the cell surface, c-kit protein was detectable at very low levels in only 1 of 5 rhabdomyosarcoma cell lines and was not up-regulated by RA or TNF-alpha. Addition of anti-c-kit and anti-SCF blocking antibodies, or of exogenous SCF did not alter the in vitro growth ability of rhabdomyosarcoma cells. In conclusion, our data show that rhabdomyosarcoma cells produce consistent amounts of SCF but did not demonstrate autocrine growth modulation. SCF secretion may thus have a paracrine, rather than an autocrine activity in this tumor.
Int J Cancer 1998 Nov 09
PMID:Production of stem cell factor and expression of c-kit in human rhabdomyosarcoma cells: lack of autocrine growth modulation. 979 32

Early clinical trials of growth factor augmentation of induction chemotherapy for acute myeloid leukemia have yielded variable results. To test the hypothesis that this heterogeneity is a consequence of the pleiotropic effects of growth factors on leukemic cell biology, we measured the effects of in vivo interleukin 3 (IL-3) administration on leukemic cell proliferation and drug sensitivity. Thirty-four patients with acute myeloid leukemia with high-risk features or advanced myelodysplasia received IL-3 as a continuous infusion beginning 3 days prior to chemotherapy and continuing for the duration of intensive induction therapy. Bone marrow cells were studied prior to and after 3 days of IL-3 administration to assess changes in overall and leukemic progenitor cell [leukemia colony-forming unit (CFU-L)] proliferation, and progenitor cell sensitivity to 1-betad-arabinofuranosylcytosine. The median fold increase in overall leukemic cell proliferation in response to IL-3, assessed as expression of the nuclear antigen Ki67 in 28 patients, was 1.2. The median fold increase in percentage of cells in S phase (assessed in 29 patients) was 1.3. Despite the increase in overall cell proliferation in 70% of cases, CFU-L number increased in only 4 of 20 patients successfully studied (median day 4:day 1 ratio of CFU-L number, 0.6). While this suggests possible terminal differentiation of leukemic progenitor cells, expression of CD34, HLA-DR, c-kit, CD15, and CD14 were not consistently affected by the cytokine. 1-betad-Arabinofuranosylcytosine sensitivity of CFU-L increased significantly in 30% of cases, decreased in 30%, and was unchanged in 40%. Changes in overall cell proliferation (Ki67 expression) and CFU-L were independent predictors of change in 1-beta-d-arabinofuranosylcytosine sensitivity; increase in percentage of cells in S phase in response to IL-3 was correlated with attainment of complete remission. While these findings support the concept of cell cycle recruitment, IL-3 has marked pleiotropic effects on proliferation, differentiation, and survival of leukemic progenitors which make the clinical impact of in vivo cytokine administration for individual patients difficult to predict.
Clin Cancer Res 1995 Mar
PMID:Impact of in vivo administration of interleukin 3 on proliferation, differentiation, and chemosensitivity of acute myeloid leukemia. 981 85

The receptor tyrosine kinase c-kit is necessary for normal hematopoiesis, the development of germ cells and melanocytes, and the pathogenesis of certain hematologic and nonhematologic malignancies. To better understand the regulation of the c-kit gene, a detailed analysis of the core promoter was performed. Rapid amplification of cDNA ends (RACE) and RNase protection methods showed two major transcriptional initiation sites. Luciferase reporter assays using 5' promoter deletion-reporter constructs containing up to 3 kb of 5' sequence were performed in hematopoietic and small-cell lung cancer cell lines which either did or did not express the endogenous c-kit gene. This analysis showed the region 83 to 124 bp upstream of the 5' transcription initiation site was crucial for maximal core promoter activity. Sequence analysis showed several potential Sp1 binding sites within this highly GC-rich region. Gel shift and DNase footprinting showed that Sp1 selectively bound to a single site within this region. Supershift studies using an anti-Sp1 antibody confirmed specific Sp1 binding. Site-directed mutagenesis of the -93/-84 Sp1 binding site reduced promoter-reporter activity to basal levels in c-kit-expressing cells. Cotransfection into Drosophila SL2 cells of a c-kit promoter-reporter construct with an Sp1 expression vector showed an Sp1 dose-dependent enhancement of expression that was markedly attenuated by mutation of the -93/-84 site. These results indicate that despite the fact that the human c-kit promoter contains multiple potential Sp1 sites, Sp1 binding is a selective process that is essential for core promoter activity.
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PMID:Selective Sp1 binding is critical for maximal activity of the human c-kit promoter. 983 19

Gastrointestinal stromal tumour (GIST) is the designation used here to identify the most common subset of gastrointestinal mesenchymal tumours specific to those sites. These tumours have unique histological, immunophenotypic and molecular genetic features that set them apart from typical smooth muscle tumours and schwannomas; however, by tradition, they have been classified as GI-smooth muscle tumours, or stromal tumours/smooth muscle tumours. GISTs occur predominantly in persons over 40 years of age with an equal sex incidence. Benign GISTs outnumber the malignant ones by a margin of 10:1. GISTs occur throughout the gastrointestinal tract, but are most common in the stomach (60-70%) and small intestine (30%). GISTs are rare in esophagus, colon and rectum. Histologically they may show a spindle cell or epithelioid pattern (the former largely corresponds with the designation of cellular leiomyoma and the latter with that of leiomyoblastoma). Immunohistochemically most GISTs are positive for CD34 and c-kit protein (CD117); the latter is quite specific for GISTs among mesenchymal tumours. Genetically GISTs commonly show DNA losses in the long arm of chromosome 14, and c-kit gene mutations occur at least in some cases. c-kit is also expressed in the interstitial cells of Cajal, the gastrointestinal pacemaker cells, and relationship of GISTs to these cells has been proposed recently. GISTs differ histologically, immunohistochemically and genetically from typical (esophageal) leiomyomas that are negative for c-kit and CD34 and neither show DNA-losses in 14q nor c-kit mutations. Evaluation of malignancy of GISTs is based on mitotic count, tumour size and extra-gastrointestinal spread. Tumours with mitotic counts higher than 5/10 high power fields or larger than 10 cm have a significant risk for recurrence and metastasis and are considered histologically malignant; however, some tumours with mitotic activity < 1/10HPF may metastasize indicating some uncertainty in malignant potential of GISTs, especially those larger than 5 cm.
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PMID:Gastrointestinal stromal tumours. 989 65

Melanoma cells in culture express a variety of growth factors and cytokines and some of their autocrine and paracrine roles have been investigated. However, less information is available on the potential dynamic changes in expression of these molecules on cells during melanoma development and progression in situ. Using immunohistochemistry, we tested 40 nevi and primary and metastatic melanoma lesions for the expression of 10 growth factors and cytokines and the respective receptors representing 10 cell surface molecules. Nevi and thin (< 1 mm) primary melanomas showed little expression of ligands except weak reactivity of tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8) and reactivity of TGF-betaR and c-kit. Marked up-regulation of growth factors, cytokines and receptor expression was observed in thick (> 1 mm) primary melanomas, which were stained with polyclonal or monoclonal antibodies (MAbs) for IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha, TGF-beta, granulocyte-macrophage colony-stimulating factor (GMCSF) and stem cell factor (SCF), but not IL-2. Metastases showed similar expression patterns except that SCF was absent. Co-expression of ligand and receptor was observed for TGF-beta, GM-CSF and IL-6, suggesting an autocrine role for these ligands. TNF-alpha appears to be a marker of benign lesions; IL-6 and IL-8 expression is associated with biologically early malignancy; TGF-beta, GM-CSF and IL-1alpha are highly expressed in biologically late lesions; and TNF-beta is an apparent marker of metastatic dissemination. Our results indicate that melanoma cells utilize cascades of growth factors and cytokines for their progression.
Int J Cancer 1999 Apr 20
PMID:Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. 1009 49

We have used proviral tagging in tumor-prone transgenic mice to identify collaborating oncogenes and genes contributing to tumor progression. This has yielded a series of oncogenes that could be assigned to different complementation groups in transformation: the myc, Pim, Bmi1, and Frat1 complementation groups. Frat1 is involved in tumor progression and appears to function in the Wnt signaling pathway. Overexpression of Fratl confers a growth advantage to transplanted tumor cells in vivo and to cells grown in vitro at high density. Frat1 might exert its activity by impairing the kinase activity of Gsk3beta, which is involved in the degradation of beta-catenin. Pim genes appear to act in tumor initiation and show strong synergism with myc in lymphomagenesis. Overexpression of Pim1 can also overcome some of the proliferative defects caused by defective interleukin signaling supporting a role of Pim1 in cell proliferation. We have applied proviral tagging in compound mutant Emu-myc/Pim1-/-/Pim2-/- mice to identify genes that can complement for the loss of Pim1 and Pim2 and, therefore, are able to synergize with c-myc in lymphomagenesis. A number of new as well as known genes have been found by this "complementation tagging." The latter included c-kit, Tp12, and cyclin D2, suggesting that Pim kinases might act upstream of or parallel to these known proto-oncogenes.
Cancer Res 1999 Apr 01
PMID:Identification and characterization of collaborating oncogenes in compound mutant mice. 1019 95

Spontaneous mast cell tumors (MCT) are the most common malignant neoplasm in the dog, representing between 7% and 21% of all canine tumors, an incidence much higher than that found in humans. These tumors often behave in an aggressive manner, metastasizing to local lymph nodes, liver, spleen, and bone marrow. The proto-oncogene c-kit is known to play a critical role in the development and function of mast cells. Point mutations in the kinase domain of c-kit leading to tyrosine phosphorylation in the absence of ligand binding have been identified in three mastocytoma lines, (P815, RBL, and HMC-1), and some human patients with various forms of mastocytosis. We now demonstrate that although c-kit derived from canine MCT did not contain the previously described activating point mutations, 5 of the 11 tumors analyzed possessed novel mutations consisting of tandem duplications involving exons 11 and 12. We also show that one such duplication, detected in a canine mastocytoma cell line, was associated with constitutive phosphorylation of c-kit protein (KIT), suggesting that these mutations may contribute to the development or progression of canine MCT.
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PMID:Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit. 1021 Mar 27

We genetically connected the extracellular domain of human stem cell factor to the Fc-portion of human IgG1. The chimeric recombinant stem cell factor IgG1 fusion protein (rSCF-IgG1) had an apparent approximately Mr 190,000 and consisted of three identical covalently linked subunits. It specifically bound to c-kit and the high affinity Fc gamma receptor, respectively. Liquid phase rSCF-IgG1 was, on a molar basis, about eight times more potent than native human rSCF in stimulating the proliferation of c-kit-positive leukemic cell lines and of nonmalignant CD34-positive hematopoietic progenitor cells. Although the effective dose conferring half maximum of [methyl-3H]thymidine uptake by liquid phase and solid phase-bound rSCF-IgG1 were comparable, the plateau level of [methyl-3H]thymidine uptake by malignant cells was decreased by the latter, whereas proliferation of nonmalignant progenitor cells was supported. Liquid phase rSCF-IgG1 had a 2-fold increased potential to maintain primitive nonmalignant progenitor cells in stroma-free long-term culture compared with rSCF. Liquid phase rSCF-IgG1 caused enhanced and prolonged receptor phosphorylation and a more rapid down modulation of c-kit. Our data support the concept that solid phase-attachment of rSCF-IgG1 is sufficient for alteration of biological function and that rSCF-IgG1 partially blocks SCF-stimulated malignant cell growth while supporting normal progenitor cells.
Cancer Res 1999 Jun 15
PMID:Differential effects of a stem cell factor-immunoglobulin fusion protein on malignant and normal hematopoietic cells. 1038 56


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