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 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.
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PMID:New understanding of the pathogenesis of CML: a prototype of early neoplasia. 952 44

Three-color immunofluorescence cytometry was used to quantify the expression of different adhesion molecules on CD34+ cells of steady-state bone marrow (BM) and peripheral blood stem cells (PBSC) after mobilizing with G-CSF (10 micrograms/kg/body weight) in nine cancer patients undergoing high-dose chemotherapy with subsequent autologous blood stem cell rescue. The expression rate of each adhesion molecule on CD34+ cells showed great inter-individual variations. High expression (> 50%) on CD34+ cells from PBSC and BM was found for CD58 (leukocyte function-associated antigen-3), CD31 (platelet-endothelial cell adhesion molecule-1), CD11a (leukocyte function-associated antigen-1) and CD49d (very late activation antigen-4); a moderate expression (20%-40%) was seen for CD49e (very late activation antigen-5), CD62L (leukocyte-endothelial cell adhesion molecule), CD54 (ICAM-1) and CD117 (c-kit). c-kit, CD58, CD62L and CD49d were less expressed on CD34+ cells of PBSC than of BM, the difference being statistically significant for CD49d (p < 0.05). CD49e and CD37 were expressed more in PBSC than BM without being statistically significant. The mean fluorescence intensity for all adhesion molecules on CD34+ cells did not differ significantly between PBSC and BM. The significantly lower expression of CD49d on G-CSF-mobilized PBSCs might suggest that downregulation of this molecule may be involved in the process of peripheral stem cell mobilization.
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PMID:Difference between expression of adhesion molecules on CD34+ cells from bone marrow and G-CSF-stimulated peripheral blood. 947 47

Effective hematopoiesis is usually induced by interactions between hematopoietic progenitor cells (HPC) and stromal cells. In cord blood (CB), umbilical vein endothelial cells (HUVEC) can support HPC as a stromal microenvironment. EC activated mainly by IL-1 and TNFalpha produce a variety of cytokines and growth factors such as IL-1, IL-4, IL-6, GM-CSF and G-CSF. Since HPC express c-kit on their surface, the SCF produced by HUVEC plays an important role in the hematopoiesis of CB. We examined the expression of cytokines and growth factors on HUVEC by PCR. Resting HUVEC expressed high level of SCF, and low levels of IL-6, IL-7, and IL-8. Thus, a variety of cytokines and growth factors are produced by EC, and this cytokine network is thought to play an important role in regulating hematopoiesis. Activated EC can also express various adhesion molecules including E-selectin, VCAM-1 and ICAM-1, and facilitate the adhesion of hematopoietic cells to the endothelium. Furthermore, the interaction of CB cells with HUVEC has recently been shown in vitro. We previously showed that the culture media of HUVEC induced high numbers of colony formation. Suitable cytokine productions are thus provided to HPC by the interaction of HUVEC and cord MNC. On the basis of these findings, several mechanisms to support hematopoiesis in CB can be considered. Specific growth factors produced by EC bind to HPC to induce proliferation. While cell-cell interactions involve adhesion of HPC to HUVEC via adhesion molecules, and the adhesion of HPC to EC will facilitate interaction with cytokines and growth factors. Thus HPC in CB proliferate and are maintained by growth factors, and adhesion molecules produced by HUVEC, and HPC themselves.
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PMID:Role of umbilical vein endothelial cells in hematopoiesis. 972 Jul 15

Histogenetically, the thymus is the primary lymphopoietic organ and provides an optimal microenvironment for the differentiation of T lymphocytes, independently of the influence of foreign antigens. Lymphocytes with diverse potential are produced in a protective microenvironment optimal for their maturation, whose dual cellular network is provided by endodermally derived RE cells and numerous ectomesenchymal cells derived from the neural crest. The full development of intrathymic hematopoiesis depends upon the successful completion of a series of well coordinated cellular interactions between widely divergent (in terms of origin) cells [epithelium (primitive pharynx); ectomesenchyrne (neural crest); and PHSCs (yolk sac, fetal liver)]. The cells of the thymic epithelial primordium do not proliferate in the absence of "inductive" interactions with the ectomesenchyme. Moreover, the nature of the mesenchyme determines the behavior of the thymic epithelial anlagen. The ectomesenchymal origin of chemotactic stem cell factor secretion, responsible for hemopoietic stem cell immigration, is a distinct possibility. The human thymus is a generalized hematopoietic tissue with between 7 to 9 weeks of ontogenesis. In human and dog fetuses various elements of mammalian hematopoiesis were identified intrathymically: B lymphocytes, plasma cells, erythropoietic and granulocytopoietic (neutrophils and eosinophils) cells, antigen presenting dendritic cells, and mast cells. Our light and ultrastructural (transmission and scanning), as well as immunocytochemical observations have established that during the embryonal and fetal period, the thymus is seeded by pluripotent, yolk sac derived PHSCs characterized by the following immunophenotype CD34+CD43+CD38-Lin-HLA-DR+CD69+. Stem cell c-kit tyrosine kinase (also referred to as mast cell growth factor, stem cell factor, or steel factor) in combination with autocrine and paracrine growth factors and cytokines (IL-3, IL-4, IL-5, IL-6, IL-7, G-CSF, etc.) stimulates myelopoiesis, including erythropoiesis, as well as lymphopoiesis. These hematopoietic growth factors are produced by activated lymphoblastic cells and stromal RE cells under the influence of immunoneuroendocrine regulation, supported by the finding that experimental or spontaneous, in vivo neural crest ablation during early mammalian ontogenesis always results in an abnormal development of the thymus, as well as the heart and great vessels, thyroid, and parathyroid glands.
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PMID:Intrathymic non-lymphatic hematopoiesis during mammalian ontogenesis. 989 Dec 23

We have evaluated the immunophenotype, functional activity and clonogenic potential of CD34+ cells from peripheral blood (PB) of normal donors before and after 4 and 6 days of G-CSF administration. The percentage and absolute number of CD34+ cells significantly increased at days 4 and 6 of G-CSF administration, compared to the steady-state level (P < 0.0001). Two-colour fluorescence analysis showed, at days 4 and 6, a lower proportion of CD34+/c-kit+ compared to the steady-state level (P < 0.0001), but a similar expression of CD13, CD33, CD38, HLA-DR and Thy-1 antigens on CD34+ cells. The expression of adhesion molecules on CD34+ cells revealed a significant reduction of CD11a (P = 0.009), CD18, CD49d and CD62L (P < 0.0001) at days 4 and 6, compared to the baseline level. Three-colour staining showed a reduction of the more immature compartment (34+/DR-/13-) and an increase of the more differentiated compartment (34+/DR+/13+). Downregulation of VLA-4 during mobilisation was seen almost exclusively on more committed cells (34+/13+); downregulation of CD62L, on the contrary, was observed on both early progenitors (34+/13-) and more committed cells (34+/13+). The expression of 34+/VLA-4+ decreased on both c-kit+ and c-kit- cells, while the expression of 34+/62L+ decreased on the c-kit+ cells only. In vivo administration of G-CSF reduced the adherence capacity of CD34+ cells to normal BM stroma; in vitro incubation with SCF or IL-3 enhanced the expression of CD49d on CD34+ cells, while GM-CSF reduced the expression of CD62L. SCF was the only cytokine able to induce a significant increase of CD34+ cell adherence to preformed stroma. Pre-incubation with the blocking beta2 integrin monoclonal antibody caused a reduction of CD34+ cell adherence. In conclusion, the decrease of CD49d expression on mobilized CD34+ cells correlates with a poor adhesion to BM stroma; CD34+ cells incubated in vitro with SCF showed, conversely, a higher expression of CD49d and a greater adherence capacity on normal preformed stroma.
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PMID:Modulation of VLA-4 and L-selectin expression on normal CD34+ cells during mobilization with G-CSF. 1003 43

Mobilization of haemopoietic precursor cells into the circulation by the combination of cytokines, stem cell factor (SCF) and G-CSF in previously untreated patients with carcinoma of the breast resulted in increased yield of collected peripheral blood precursor cells (PBPC). This mobilization of PBPC by SCF with G-CSF lasted several days after ceasing the cytokines in comparison to the rapid fall of PBPC after ceasing G-CSF. Possible mechanisms for this increased and prolonged mobilization were investigated. Immunological phenotyping with CD38, Thy-1 and MDR-1 of the CD34-positive mobilized PBPC detected no difference in maturity compared to PBPC mobilized by G-CSF alone. However, the down-regulation of c-kit, which is associated with the mechanism of mobilization, was much greater in the PBPC mobilized by SCF and G-CSF. The potential clinical implication of increased and prolonged mobilization is increased yield, allowing transplantation of heavily pre-treated patients, transplantation with PBPC from a single apheresis, or PBSC support for multiple courses of high-dose therapy from one mobilization procedure.
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PMID:Prolonged release and c-kit expression of haemopoietic precursor cells mobilized by stem cell factor and granulocyte colony stimulating factor. 1019 40

We report the cellular characteristics of cells from three patients with de novo acute myelocytic leukaemia (AML) with t(16;21)(p11;q22), two M4 and one M5a according to the FAB classification, and two permanent cell lines with t(16;21)(p11;q22), TSU1621MT and YNH-1. The FUS/ERG fusion mRNA was demonstrated in all cases by reverse transcriptase-polymerase chain reaction (RT-PCR). The immunophenotypes of the AML cells, and YNH-1 and TSU1621MT cell lines with t(16;21) were characterized as CD34+CD33+CD13+CD11b+CD18+CD56+ HLA-DR-/+. Cells from all samples strongly expressed c-kit, granulocyte colony-stimulating factor receptor (G-CSFR), c-fms (macrophage colony-stimulating factor receptor), interleukin-3 receptor alpha chain (IL-3Ralpha), and granulocyte macrophage colony-stimulating factor receptor alpha chain (GM-CSFRalpha), and these data corresponded well to the growth responsiveness to the cytokines. IL-2Ralpha expression was also found in all t(16;21) samples, but IL-2 did not act on the proliferation of the leukaemic cells in in vitro cultures. G-CSF distinctly promoted the proliferation of leukaemic cells of t(16;21) AML, but did not enhance the expression of MPO and neutrophil differentiation of these cells. Our findings indicate that AML cells with t(16;21) preserve stem cell properties such as CD34 and c-kit expression, and suggest that they have the potential to differentiate into a monocytic lineage. The relationship between the unique cellular characteristics (especially CD56 and IL-2Ralpha expression) and FUS/ERG protein remains undetermined.
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PMID:Myeloid differentiation antigen and cytokine receptor expression on acute myelocytic leukaemia cells with t(16;21)(p11;q22): frequent expression of CD56 and interleukin-2 receptor alpha chain. 1035 36

The regulation of cell differentiation and cell death in crucial to the generation of hematopoietic cells both in vitro and in vivo. The biologic role of stem cell factor (SCF) in hematopoietic cell development is not well known. We monitored the survival, proliferation and differentiation of mouse hematopoietic cells in culture in the presence of SCF. Examination of colony formation, MTT and thymidine killing of mouse bone marrow indicated that SCF is mainly a survival factor. Our results show that SCF maintains cells in a "undifferentiated" state. Committed granulocytic and monocytic progenitors (CFU-GM) survive for seven days in the presence of SCF alone, under conditions where no maturing granulocytic monocytic cells could be recovered. On transfer to GM-CSF containing cultures, these cells proliferate and differentiate terminally. Together, our data indicate that SCF induces survival in hematopoietic progenitors. Furthermore, SCF favors the survival of granulocytic progenitors over that of monocytic progenitors. In the absence of later acting factors such as GM-CSF, cells that progress beyond the CFU-GM stage lose c-kit expression and die by default. Hence, lack of cell expansion in the presence of SCF by itself is due to constant cell proliferation and survival, which is counterbalanced by cell death. In contrast, the presence of both SCF and GM-CSF allows for the continuous survival and expansion of hematopoietic progenitor cells in culture, as well as favoring their terminal differentiation along granulocytic and monocytic pathways. Furthermore, GM-CSF induces colonies of macrophages that produce G-CSF and IL-6, two molecules involved in granulopoiesis, and these in turn stimulate granulocyte colony formation. Finally, our data suggest that survival signals by SCF are crucial during the differentiative process of granulocytes, giving strength to deterministic model.
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PMID:[Stem cell factor (SCF) supports granulocyte progenitor survival in mouse bone marrow cultures]. 1041 May 90

The biological effects of flt3-L, and the expression of its tyrosine kinase receptor (flt3, CD135) were investigated on the immature subsets of human circulating peripheral blood progenitors obtained from cancer patients or normal volunteer donors, after mobilization with rhG-CSF or chemotherapy. flt3 was expressed at low levels, and its expression increased concomitantly with expression of CD38 within the CD34+ cell population. Despite this low-level expression, flt3-L exerted synergistic effects with a combination of c-kit ligand, IL-3, IL-6, GM-CSF and G-CSF, mainly to induce proliferation of CD34+/CD38- cells. In addition, flt3-L increased the detection of HPP-CFC, both immediately after cell selection, and after 7 and 14 d of cultures. We conclude that flt3-L is active on circulating early mobilized haemopoietic progenitors, despite the low- level expression of its receptor.
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PMID:Early progenitor cells from human mobilized peripheral blood express low levels of the flt3 receptor, but exhibit various biological responses to flt3-L. 1046 May 91

The yield of CD34+ PBPC and colony-forming units-granulocyte-macrophage (CFU-GM) in leukapheresis products and the expression of the adhesion molecules CD11a, CD31, CD49d, CD49e, CD54, CD58, CD62L, c-kit (CD117), Thy-1 (CD90), CD33, CD38, and HLA-DR on CD34+ PBPC were analyzed in patients with cancer of the testis (n = 10), breast cancer (n = 10), Hodgkin's disease (n = 20), high-grade (n = 20) and low-grade (n = 20) non-Hodgkin's lymphoma, and healthy donors (n = 20) undergoing G-CSF (filgrastim)-stimulated PBPC mobilization. For each disease entity, G-CSF was administered in two different doses, 10 microg G-CSF/kg body weight (BW)/day s.c. vs. 24 microg G-CSF/kg BW s.c./day in steady-state condition. Data were compared for each dose group separately. Patients with cancer of the testis and breast cancer mobilized significantly more CD34+ cells than patients with high-grade and low-grade non-Hodgkin's lymphoma and Hodgkin's disease (p<0.05). Correspondingly, expression of CD49d on CD34+ PBPC was significantly lower in the same patients with cancer of the testis compared with high-grade and low-grade non-Hodgkin's lymphoma and Hodgkins' disease and in patients with breast cancer compared with high-grade and low-grade non-Hodgkin's lymphoma, Hodgkins's disease, and healthy donors. Similar results were obtained for CD49e. These data suggest that the expression of the adhesion molecules CD49d and CD49e on G-CSF-mobilized CD34+ cells of patients with solid tumors, non-Hodgkin's lymphoma, Hodgkin's disease, and healthy donors is inversely correlated with the amount of mobilized CD34+ cells.
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PMID:Expression of the adhesion molecules CD49d and CD49e on G-CSF-mobilized CD34+ cells of patients with solid tumors or non-Hodgkin's and Hodgkin's lymphoma and of healthy donors is inversely correlated with the amount of mobilized CD34+ cells. 1079 4


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