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)

Myeloproliferative disorders (MPD) constitute a group of hematopoietic neoplasms at the myeloid stem cell level. Myeloid stem cells and/or progenitor cells from MPD have been considered sensitive to hematopoietic growth factors, including erythropoietin, thrombopoietin and stem cell factor (SCF). SCF is a ligand for c-kit receptor with tyrosine kinase. We analysed the gene alteration of the c-kit extracellular domain in MPD patients by PCR-SSCP and subsequent nucleotide sequencing. The point mutation in the N-terminal part of the domain, codon 52 (Asp-->Asn), was found in two patients with primary myelofibrosis and one with chronic myelogenous leukemia. We review the literature regarding the role of SCF/c-kit system in the oncogenesis of leukemia and MPD, and then discuss the significance of our finding in the context of growth advantage of the mutated clones over the normal clones.
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PMID:c-kit Point mutation in patients with myeloproliferative disorders. 916 38

Expression of the multidrug resistance (MDR) phenotype is an independent prognostic variable in acute myeloid leukemia. Approximately 43-57% of the patients have P-glycoprotein (P-gp) expression. A major drawback with the interpretation of P-gp data in AML is the lack of coherence with different analytical assays. We have focused our efforts of P-gp detection on flow cytometry using a dual technique of P-gp staining with antibodies for the extracellular epitope (MRK16) and a functional analysis of P-gp using the rhodamine efflux assay and the effect of P-gp inhibitors such as SDZ PSC 833. This technique was combined with the staining of lineage-specific antigens such as CD34, CD56 and c-kit. In this way, various subsets of AML cells can be identified such as MRK 16+/-, CD34+/- blasts. These cells can be sorted for further analysis, such as the molecular expression of P-gp and other pleiotropic drug resistance genes.
Leukemia 1997 Jul
PMID:Assays for the analysis of P-glycoprotein in acute myeloid leukemia and CD34 subsets of AML blasts. 920 6

We investigated the mechanism of constitutive activation of c-kit receptor tyrosine kinase (KIT) found in the FMA3 murine mastocytoma cell line, and compared it with the mechanisms observed in other tumor mast cell lines (the HMC-1 human mast cell leukemia cell line, the RBL-2H3 rat mast cell leukemia cell line, and the P-815 murine mastocytoma cell line). The c-kit gene obtained from FMA3 cells was found to have 21-base deletion at the juxtamembrane domain of KIT, thereby leading to the constitutive activation of KIT. The deletion at the juxtamembrane domain resulted in constitutive dimerization of c-kit proteins, whereas the point mutation that were detected at the kinase domain of KIT in HMC-1, RBL-2H3, and P-815 cells caused constitutive activation of KIT without dimerization. These constitutively activating mutations of c-kit may play a role in development of mast cell tumors.
Leukemia 1997 Apr
PMID:Mechanisms of constitutive activation of c-kit receptor tyrosine kinase. 920 3

Self renewal and differentiation of hematopoietic stem cells is regulated by the hematopoietic microenvironment. The Stem Cell Factor (SCF) has been shown to be one of the essential factors that governs stem cell maintenance. In this abstract we describe a functional analysis of the membrane bound and soluble SCF within the context of stroma cocultures with hematopoietic cells. We report that transmembrane SCF is essential for long term growth, whereas soluble SCF supports only short term proliferation of stroma dependent hematopoietic cells. We also show that the SCF/c-kit interaction can be substituted by an unknown mechanism. To determine the molecular mechanism involved in maintenance of hematopoietic cells on stroma we analyzed the c-kit expression during coculture. We demonstrate that c-kit expression was downregulated during coculture. Downregulation was induced by the coculture itself and not by external factors.
Leukemia 1997 Apr
PMID:Role of the stem cell factor (SCF) receptor and the alternative forms of its ligand (SCF) in the induction of long-term growth by stroma cells. 920 36

The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor. It is expressed by the primitive CD34 positive haemopoietic stem cells and interacts with the Kit ligand for signal transduction. It was reported to be expressed in over 80% of acute myelogenous leukaemia (AML) patients in North America and Japan. We analyzed 20 AML patients for c-kit expression using either Northern blot analysis or flow cytometry with the YB5.B8 anti-c-kit antibodies. Only 6 out of 20 AML patients expressed the c-kit mRNA or protein product. However, a previously unreported abnormal sized 1.7-1.9 kb transcript was detected in the blast cells of 1 AML patient, 1 acute mixed lineage leukaemia patient and 1 chronic myelogenous leukaemia (CML) patient in myeloblastic transformation. Our data suggested that in most Hong Kong Chinese AML patients, leukaemia transformation may have occurred at a c-kit negative stage. Alternatively, the abnormal sized c-kit transcript that was detected in some Chinese myeloid leukaemia patients may represent an aberrant c-kit receptor that plays an important role in leukaemogenesis.
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PMID:Low frequency of c-kit expression and detection of an aberrant Kit message among Hong Kong Chinese myelogenous leukaemia patients. 921 71

The 9;22 chromosomal translocation characteristic of CML results in a fused bcr/abl gene and an abnormal fusion protein, p210bcr/abl. Relative to normal c-abl, p210bc1/abl has elevated tyrosine kinase activity that is essential for its transforming activity. We recently reported a prominent 62 kDa GAP-associated P-tyr protein and five additional consistent but less prominent P-tyr proteins as well as five more minor P-tyr proteins that are constitutively tyrosine phosphorylated in primary primitive lineage negative (lin-) chronic phase CML blasts but not in comparable primary lin- normal blasts. The GAP-associated p62 protein has now been purified, sequenced and its gene has been cloned; it is a previously unidentified protein and is currently being characterized. In analyzing P-tyr proteins in primary lin- normal blasts in response to various hematopoietic cytokines, we found a striking similarity in the tyrosine phosphorylation of four major and three minor proteins after stimulation with c-kit ligand (KL) and the P-tyr proteins that are constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other cytokines tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand, TPO, EPO) were much less active or stimulated phosphorylation of other proteins. KL/c-kit and bcr/abl have some similar activities including enhancing survival and expansion of hematopoietic progenitor cells, probably acting primarily on early progenitors at the time of lineage commitment rather than on self-renewing stem cells. Activation of growth factor receptors promote a cascade of protein phosphorylations that can ultimately result in a wide range of cellular responses. Sustained activation of discrete signaling pathways in some types of cells results in differentiation, whereas transient activation instead causes a proliferative response; in other cell types, the converse is true. It may be postulated that stem cells and primitive progenitors are at a particularly susceptible stage of development that renders them especially responsive to sustained bcr/abl-induced phorphorylation of a number of signaling proteins that are components of critical regulatory pathways, including c-kit. The affected pathways control and coordinate multiple diverse cell processes including proliferation, differentiation, maturation and apoptosis, processes that are normally tightly regulated and integrated. Perturbation of these key pathways in primitive progenitors would be expected to seriously disrupt orderly hematopoiesis and could also explain the multiple subtle pleiotropic biological abnormalities characteristically observed in later maturing CML compartments that we have collectively designated 'discordant maturation'. The true situation is undoubtedly very complex and involves interaction of multiple cytokines and signaling pathways that we are now trying to define. Constitutive downstream activation of critical pathways in susceptible early progenitors that normally require KL or other factors for activation could explain most if not all features of the disease.
Leukemia 1997 Sep
PMID:New understanding of the pathogenesis of CML: a prototype of early neoplasia. 952 44

A coculture system of a murine erythroblastic leukemia cell line (ELM-D) with its supportive stromal cell line (MS-5) was established. Long-term growth of ELM-D cells is strictly stroma cell dependent. Interaction between stem cell factor (SCF) and its receptor, c-kit, was demonstrated to be important for stroma cell-dependent growth by anti c-kit neutralizing monoclonal antibody (mAb) inhibition experiments. Significantly, soluble growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) or SCF of MS-5 stromal cells (MS-5 CM) could replace the requirement of stroma cells for a considerable period. However, ELM-D cells maintained in these growth factors underwent clonal extinction after 3-6 weeks unless contact with stroma was re-established. Furthermore, IL-3 or GM-CSF acted in a dominant manner in inducing cell death in the presence of stroma cells. Cells showing clonal extinction undergo programmed cell death and do not differentiate. These altered growth properties of ELM-D cells exposed to soluble growth factors or to stroma cells appear to be analogous to those described for T or B cells primed by antigen presenting cells and then grown in growth factors.
Leukemia 1997 Oct
PMID:The role of soluble growth factors in inducing transient growth and clonal extinction of stroma cell dependent erythroblastic leukemia cells. 932 97

P-glycoprotein (Pgp), the major mediator of multidrug resistance (MDR) has often been implicated as a poor prognostic indicator in acute myeloid leukaemia (AML). We have previously reported that high expression of the receptor tyrosine kinase c-Kit in AML is associated with poor prognosis. To determine whether the MDR phenotype is associated with high c-Kit expression, the monoclonal antibodies UIC-2 and YB5.B8, which identify Pgp and c-Kit, respectively, were used for indirect immunofluorescence labelling of 50 de novo AML specimens. Quantitative dye efflux studies using Rhodamine123 were also carried out to assess the functional drug efflux capability of these samples. Pgp expression by the majority of primary AML was comparable to that seen in subsets of cells from normal bone marrow and Spearman rank analysis showed no relationship with c-Kit expression (rs = 0.20, P = 0.16). However, c-Kit expression did show a significant correlation with Rhodamine123 efflux (rs = 0.57, P = 0.0001), suggesting that the MDR phenotype, Pgp mediated or other, may contribute to the prognostic significance of high c-Kit expression. The monoclonal antibody UIC-2 was used specifically to block Pgp activity of a limited number of leukaemic specimens and cell lines, and evidence of non-Pgp-mediated efflux was found. The existence of alternative mechanisms may explain the relatively low correlation of Pgp expression with dye efflux within the leukaemic samples (rs = 0.47, P = 0.0006) and has implications for prognosis in AML. The c-Kit ligand, stem cell factor, did not influence drug efflux activity of the nine c-Kit-positive AML specimens tested. Thus the correlation between c-Kit and the MDR phenotype in AML is likely to be a consequence of co-expression at a similar stage of differentiation, and may account for the previously observed association of high c-Kit expression with poor outcome.
Leukemia 1997 Nov
PMID:Expression of c-Kit and functional drug efflux are correlated in de novo acute myeloid leukaemia. 936 17

CD45-negative B-cell precursor acute lymphoblastic leukaemia (ALL) provides a unique model to study the stem cell compartment in ALL as leukaemic CD34-positive cells, unlike their normal counterparts, do not express CD45. By increasing the number of events analysed to 10(6), storing only the events in the region of interest (storage gate), using appropriate isotype controls and stringent washing procedures, a flow cytometric protocol was established to characterize rare CD34+ CD19- events. In eight of 12 patients (67%) with CD45-negative B-cell precursor ALL, a distinct CD34+ CD19- CD45+ candidate normal stem cell population could be detected. In one patient analysed by four-colour staining, the CD34+ CD19- CD45+ cells, unlike the CD45-negative leukaemic cells, expressed CD117 (c-kit), providing further evidence that these cells represent residual nonleukaemic normal cells. By multiparameter analysis, this population of candidate normal stem cells could be separated from contaminating leukaemic CD34+ CD19- CD45- cells, which were detected in 11 of the 12 patients within the CD34+ CD19- compartment.
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PMID:Flow cytometric identification of candidate normal stem cell populations in CD45-negative B-cell precursor acute lymphoblastic leukaemia. 950 32

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.
Leukemia 1998 Feb
PMID:Elevated expression of the proto-oncogene c-kit in patients with mastocytosis. 951 79


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