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)

A monoclonal antibody (17F11) was raised by immunization of a Balb/c mouse with leukemic blasts from a patient with acute non-lymphocytic leukemia (ANLL). This antibody recognizes most leukemic blasts of myeloid but not of lymphoid lineage and no peripheral blood cells. By screening NIH-3T3 fibroblasts transfected with the human proto-oncogene c-kit (NIH-3T3/hckit) it could be shown that 17F11 specifically recognizes the gene product P145c-kit. Immunofluorescence analysis on normal hemopoietic cells revealed that 17F11 weakly stains 1-3% of bone marrow mononuclear cells (BMMNC). By FACS sorting and colony assays it could be shown that granulocyte--macrophage progenitor cells could be enriched 10-20-fold, granulocyte progenitors 50-80-fold, and erythroid and multipotential progenitor cells 15-20-fold, in the 17F11 positive fraction. Double fluorescence analysis revealed that P145c-kit is co-expressed on 40-60% of the CD34 positive BMMNC. Finally, these data show that P145c-kit is expressed on blast cells from most patients with ANLL (26/30) and chronic myeloid leukemia in blast crisis (7/9), but is absent on blasts from patients with acute lymphoblastic leukemia expressing the T-, B-lineage, or common ALL phenotypes.
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PMID:The product of the proto-oncogene c-kit (P145c-kit) is a human bone marrow surface antigen of hemopoietic precursor cells which is expressed on a subset of acute non-lymphoblastic leukemic cells. 172 Apr 90

Chronic myelogenous leukemia (CML) cell growth may be inhibited by exposure to antisense (AS) oligodeoxynucleotides (ODN). Our initial studies targeted the c-myb protooncogene and were carried out on cells derived from patients in CML blast crisis. Subsequently, we extended these studies to cells isolated from patients in chronic disease phase. We found that c-myb AS ODN inhibited growth of CML CFU-GM in a dose dependent, sequence specific manner in approximately 75% of cases evaluated. Bcr-abl expression was either greatly decreased or nondetectable in the residual colonies and no residual leukemic CFU were demonstrable upon re-plating of treated cells. AS ODN that target the c-kit protooncogene also inhibit CML CFU and lead to downregulation of bcr-abl in responding cells in approximately 50% of cases. Therefore, AS ODN may prove to be useful purging agents. Most recently, we have treated SCID mice engrafted with bcr-abl expressing human K562 cell leukemia with phosphorothioate modified AS ODN. We have found that treated mice survive three to eight times longer than their untreated or sense treated controls. In aggregate, these results suggest that AS ODN may prove useful for both ex vivo and in vivo treatment of patients with CML.
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PMID:Potential therapeutic applications of antisense oligodeoxynucleotides in the treatment of chronic myelogenous leukemia. 750 43

The c-kit proto-oncogene is the receptor gene for the stem cell growth factor. Little is known about the distribution and role of this gene product in malignant hematopoiesis. We analysed here the expression of c-kit in myeloproliferative disorders (MPDs), including chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and idiopathic myelofibrosis (IMF) and in the myelodysplastic syndromes (MDS). The c-kit expression of peripheral blood mononuclear cells was measured both at the messenger RNA level using Northern analysis, the RNA dot blot technique with densitometric quantification, the sensitive reverse transcription polymerase chain reaction, and at the protein level using immunofluorescence with monoclonal antibodies. There was a statistically significant increase in c-kit messenger levels in CML, ET, PV, IMF, and MDS as compared with controls (healthy volunteers). The percentage of c-kit protein expressing cells was also higher than in the controls in these disorders. There was a significant correlation of the c-kit protein expression with the CD34 antigen of the cells. Expression correlated with the phase of the disease, being highest in the blast crisis of CML and in the RAEB/RAEBt phases of MDS. The data suggest that increased amounts of circulating stem/progenitor cells with c-kit receptor are found in MPDs and MDS. It is possible that elevated c-kit expression could maintain the affected clone in MPDs and MDS.
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PMID:Expression of the c-kit proto-oncogene in myeloproliferative disorders and myelodysplastic syndromes. 751 74

Autonomous, factor-independent growth and differentiation of malignant cells in preleukemic and leukemic disease states is a well-recognized phenomenon and is often associated with a poor prognosis. Mast cells are distinct hematopoietic cells and express a unique profile of antigens. Growth and differentiation of normal mast cells is dependent on mast cell growth factor (MGF), the ligand of the c-kit protooncogene product. In this study, we screened for mast cell-lineage involvement in 52 patients suffering from myeloid leukemias, myelodysplastic syndromes (MDS), systemic mastocytosis, or other diseases by probing for mast cell-related molecules (c-kit, tryptase, histamine, and MGF) and by analyzing kit ligand/MGF-independent growth of mast cells in long-term suspension culture. Of the 52 patients tested, 2 patients with refractory anemia with excess of blast cells in transformation and 1 patient suffering from chronic myeloid leukemia blast crisis (CML-BC) were diagnosed as mastocytic disease. These patients were characterized by complex chromosomal abnormalities, splenomegaly, high percentages of circulating metachromatic cells (5% to 25%), high levels of cellular tryptase (> 10 ng/10(5) peripheral blood mononuclear cells/mL) and a tryptase/histamine (ng:ng) ratio greater than 1. The metachromatic cells expressed the mast-cell-related surface antigen c-kit, but not basophil-related antigens (CD11b, CDw17). Furthermore, in these 3 patients, spontaneous, MGF-independent growth of mast cells along with spontaneous synthesis of tryptase was demonstrable in long-term culture. No autocrine production, paracrine production, or overproduction of MGF was found. The spontaneous growth of mast cells could neither be abbrogated by addition of monoclonal antibodies (MoAbs) to c-kit nor by MoAbs against MGF (< 5% inhibition), whereas factor (MGF)-dependent differentiation of mast cells in these patients could be abbrogated by MoAbs to c-kit or MoAbs to MGF (> 70% inhibition, P < .001). In addition, serum MGF levels in these patients were within the normal range and MGF could not be detected in cell-free culture supernatants. All 3 patients showed rapid progression of disease and had a survival time of less than 1 year. In conclusion, we describe a unique form of transformation in MDS and CML-BC characterized by mast cell lineage involvement and factor-independent differentiation of mast cells. This form of leukemic transformation has to be delineated from chronic myeloid leukemia with basophilia or basophil crisis, from primary mast cell leukemia, and from monocytic leukemias and myelodysplastic disorders associated with basophilia.
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PMID:Kit ligand/mast cell growth factor-independent differentiation of mast cells in myelodysplasia and chronic myeloid leukemic blast crisis. 752 72

The murine monoclonal antibody YB5.B8 (CD117) identifies a transmembrane tyrosine kinase receptor encoded by the human c-kit proto-oncogene. In this study we investigated the expression of c-kit on different types of acute leukemia to determine the degree of specificity and sensitivity of this marker for the myeloid and lymphoid lineages. C-kit was positive in over half of the 115 cases of acute leukemia studied. Overall, two thirds of AML cases expressed c-kit, whereas only one of 23 ALL patients was c-kit positive. C-kit was also positive in 16 of 19 cases of myeloid blast crisis of myeloproliferative disorders and negative in four with a lymphoid phenotype. There was no correlation between c-kit expression and the degree of myeloid differentiation by FAB subtypes or other markers. We conclude that c-kit is a specific marker for the myeloid lineage, which is expressed early during hematopoietic differentiation and can aid the diagnosis of AML in difficult cases. More patients need to be tested to establish whether the expression of c-kit may define AML subgroups of prognostic significance.
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PMID:C-kit receptor (CD117) expression in acute leukemia. 860 74

CD117 is a transmembrane protein receptor encoded by the c-kit proto-oncogene. The CD117 ligand is stem cell factor, an important hematopoietic regulator. CD117 is present on approximately 4% of normal bone marrow mononuclear cells and in acute myelogenous leukemia (AML) and chronic myelogenous leukemia in myeloid blast crisis, but rarely in acute lymphoblastic leukemia (ALL). Initially viewed as a primitive myeloid marker, CD117 has been identified in all FAB subtypes of AML and may predict poor outcome. CD34, a primitive stem cell marker, may also predict poor outcome. The aim of this study was to examine the relationship between CD117 and CD34 expression on leukemic blasts and to determine whether CD117 is related to lymphoid-associated antigen (LAA) expression in AML. Consecutive bone marrow samples were studied from cases of AML (30 cases), myelodysplastic syndromes (MDS) (4 cases), myeloproliferative disorders in blast crisis (MPD-BC) (6 cases), and ALL (5 cases). Cases were diagnosed according to FAB criteria and included M0 (3 cases), M1 (2 cases), M2 (13 cases), M3 (1 case), M4 (6 cases), M5 (3 cases), M6 (1 case), AML NOS (1 case), RAEB (3 cases), and RAEB-T (1 case). CD117 and CD34 were analyzed by multiparameter flow cytometry. Blasts in 10 de novo AML samples were CD117+/CD34+ in 4 cases, CD117+/CD34-in 3 cases, CD117-/CD34+ in 1 case, and CD117-/ CD34- in 2 cases. Blasts in 20 cases of relapsed AML were CD117+/ CD34+ in 13 cases, CD117+/CD34- in 6 cases, and CD117-/CD34+ in 1 case. Blasts in MDS were CD117+/CD34+ in 3 cases, CD117-/ CD34+ in 1 case. Blasts in MPD-BC were CD117+/CD34+ in 4 cases, CD117-/CD34+ in 2 cases. Blasts in ALL were CD117+/CD34+ in 1 case, CD117-/CD34+ in 1 case, CD117-/CD34- in 3 cases. Of 26 cases of CD117+ AML, CD4 was expressed in 15 (58%) cases, CD7 in 7 (27%) cases, and CD2 in 2 (8%) cases. CD117/CD34 expression did not correlate with FAB subtype of AML. CD117 is borne on most leukemic blasts of myeloid origin (in this study, 87% of AML, 80% of MPD-myeloid BC, and 75% of MDS) and does not exclude expression of LAA. Although CD117 is a receptor for stem cell factor, its expression does not appear to correlate with CD34 positivity.
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PMID:CD117/CD34 expression in leukemic blasts. 871 72

The c-kit proto-oncogene encodes a 145 kd tyrosine kinase transmembrane receptor, which plays a key role in haemopoiesis. The c-kit has been classified as CD117 and is especially useful in the differential diagnosis of acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). We analysed 104 consecutive cases (55 AML, 23 B-cell lineage ALL, three T-cell ALL, 11 blast crisis of chronic myeloproliferative disorders and 12 cases of myelodysplastic syndromes with more than 10% of blasts) referred to our Hospital for immunophenotypic diagnosis and compared the expression pattern of CD13, CD33 and CD117 using the same fluorochrome (phycoerythrin-PE). The recommendations of the EGIL group were followed in order to establish lineage involvement of the blastic population. The threshold used to assign positivity for CD117 was 10%. Bcr/abl, TEL/AML-1 and MLL rearrangements were assessed by molecular methods. CD117 expression was detected in 91% of AML and MDS. All the negative cases corresponded to acute monocytic leukemias. The calculated specificity for myeloid involvement was 0.86 for CD117, 0.36 for CD13 and 0.44 for CD33 (P < 0.005). CD117 was also positive in four cases of ALL. None of these cases showed bcr/abl or MLL rearrangements. In the light of these findings, CD117 expression should yield a higher score, at least one point, in the system currently applied for the diagnosis of biphenotypic acute leukemias (BAL) as its myeloid specificity is greater than that of CD13 and CD33. Moreover, its absence in AML could identify two subgroups of M5b cases. The coexpression of CD117 with cytoplasmic CD79a is often associated with CD7 reactivity, suggesting a stem cell disorder. CD117 should be included on a routine basis for the immunophenotypic diagnosis of acute leukemias.
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PMID:Enhanced myeloid specificity of CD117 compared with CD13 and CD33. 1022 19

Tyrosine kinases are enzymes that regulate mitosis, differentiation, migration, neovascularization, and apoptosis. Their spectrum and association with specific malignancies offer multiple targets for therapeutic intervention. Chronic myelogenous leukemia (CML) represents an ideal target for a therapy using a selective inhibitor of the BCR-ABL tyrosine kinase. The 2-phenylpyrimidine derivative STI571 was rationally designed to inhibit ABL and BCR-ABL tyrosine kinase activities through competitive ATP-binding pocket interactions. Phase II data demonstrate hematologic and cytogenetic responses in interferon refractory chronic-phase, accelerated-phase and blast crisis patients. However, long-term observation is needed to confirm that response data result in prolongation of survival. STI571 is being studied in other malignancies, including leukemias characterized by expression of alternate molecular forms of BCR-ABL and those expressing protein tyrosine kinases with ATP-binding pockets structurally similar to ABL, e.g. c-kit and PDGF-R. Gastrointestinal stromal tumor (GIST) cells overexpress the stem cell factor receptor CD117, the product of the proto-oncogene c-kit. Inhibition of c-kit in vivo results in an immediate metabolic change of the tumor cells, detectable by positron emission tomography. Since c-kit overexpression is inhibited in small-cell lung cancer cell lines, a study with STI571 as second-line therapy of c-kit-positive small-cell lung cancer is in progress. Clinical studies are ongoing in malignancies associated with an enhanced activity of the PDGF-R, such as highgrade glioma, prostate cancer and leukemias with rearrangements of PDGF-R. The development of selective tyrosine kinase inhibitors is considered a promising approach for the design of new drugs. Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors.
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PMID:[Selective inhibition of tyrosine kinases - a new therapeutic principle in oncology]. 1160 Aug 16

The Philadelphia chromosome found in leukemia cells of chronic myelogenous leukemia (CML) patients is produced by translocation between chromosomes 9 and 22, resulting in expression of a chimera protein of Bcr and Abl kinase in the cytoplasm. Bcr-Abl kinase attracted oncology researchers as a molecular target for CML therapy, and a variety of small Abl kinase inhibitors were synthesized. STI571 (imatinib mesylate) was produced by modification of 2-phenylaminopyrimidine, a core structure of protein kinase C inhibitor, to improve selectivity, stability, solubility, and bioavailability. STI571 competitively binds to the ATP binding site of Bcr-Abl kinase and inhibits Abl tyrosine kinase activity. STI571 showed significant efficacy in the clinical study with CML patients at all stages: chronic phase, accelerated phase, and blast crisis. More than 90% of the patients showed good hematologic response to STI571. STI571 is also a potent inhibitor of a receptor-type c-Kit tyrosine kinase. Therefore, STI571 was examined for therapeutic efficacy against malignant Gastro-Intestinal Stromal Tumors (GIST), which are mainly caused by aberrant expression of a mutated c-Kit that is constitutively active without binding of a ligand, stem cell factor (SCF). More than a half of the metastatic GIST patients enrolled in the clinical study responded to STI571. Thus, STI571 is now used as a therapeutic drug for both CML and GIST in more than 80 countries worldwide. Certain point mutations in the ATP binding site were found to be a cause of resistance to STI571 in both Bcr-Abl and c-Kit kinases. Therefore, it would be better to make a precise therapeutic strategy with STI571 based on the gene analysis data. It is also expected that it will be possible to design an inhibitor to overcome such resistance by using the structural information on the mutants.
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PMID:Tyrosine kinase inhibitor as a therapeutic drug for chronic myelogenous leukemia and gastrointestinal stromal tumor. 1463 2

Bcr-Abl kinase is known to reverse apoptosis of cytokine-dependent cells due to cytokine deprivation, although it has been controversial whether chronic myeloid leukemia (CML) progenitors have the potential to survive under conditions in which there are limited amounts of cytokines. Here we demonstrate that early hematopoietic progenitors (Sca-1(+) c-Kit(+) Lin(-)) isolated from normal mice rapidly undergo apoptosis in the absence of cytokines. In these cells, the expression of Bim, a proapoptotic relative of Bcl-2 which plays a key role in the cytokine-mediated survival system, is induced. In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate. In addition, the expression levels of Bim are uniformly low in cell lines established from patients in the blast crisis phase of CML, and imatinib induced Bim in these cells. Moreover, small interfering RNA that reduces the expression level of Bim effectively rescues CML cells from apoptosis caused by imatinib. These findings suggest that Bim plays an important role in the apoptosis of early hematopoietic progenitors and that Bcr-Abl supports cell survival in part through downregulation of this cell death activator.
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PMID:Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors. 1522 21


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