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)

There is increasing evidence for an interaction between acute leukemia cells and the microenvironment of the bone marrow. Blast cells from cases of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) bind to cellular and extracellular matrix components of the bone marrow stroma. In AML, adhesion to stroma is mediated by the combined action of beta 1 (principally VLA-4) and beta 2 integrins, while in precursor-B ALL VLA-4 and VLA-5 integrins play a major role. Adhesion molecules such as CD31, CD44, non-beta 1, beta 2 integrins, growth factor receptors such as c-kit, and other molecules are also likely to play a role. Binding of acute leukemia blasts to ligands on stroma has several pathophysiological consequences. Stromal contact is able to inhibit programmed cell death (apoptosis) in a proportion of cases of both AML and ALL. In ALL, diffusible molecules derived from stroma appear to contribute. Marrow stroma also plays a part in regulating leukemic cell proliferation. While this is partly due to stromal production of hemopoietic growth factors, in soluble or transmembrane form or bound to extracellular matrix, signalling mediated directly by binding of adhesion molecules on leukemic cells may also have a role. Contact of ALL blasts with marrow fibroblasts is followed by migration of leukemic cells, utilizing VLA-4 and VLA-5 integrins, potentially allowing homing of blasts to favourable microenvironmental sites, or controlling egress into the circulation. AML cells compete for stromal binding sites with natural killer cells and cytotoxic lymphocytes, which are known to inhibit their clonogenic growth. We speculate that these complex interactions between leukemic blasts, cellular and matrix components of stroma, and cytotoxic lymphocytes, play a critical role in determining the fate of small numbers of leukemic cells surviving after cytotoxic chemotherapy.
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PMID:Interaction of acute leukemia cells with the bone marrow microenvironment: implications for control of minimal residual disease. 858 Aug 10

Kit, the receptor for stem cell factor (SCF) and the product of the c-kit proto-oncogene, is expressed on fetal liver-derived mast cell progenitors when cultured with SCF. Decreased levels of Kit on the surface of human fetal liver-derived mast cells after exposure to recombinant human SCF were demonstrated by flow cytometry using the YB5.B8 mAb against Kit. Internalization of Kit along with SCF appears to be the principal means by which Kit is lost from the mast cell surface. Neither the beta 3-integrin CD51/CD61 (alpha v beta 3), nor the beta 1-integrins CD49d,e/CD29 (VLA-4 and -5) appeared to be internalized along with Kit-SCF complexes. Reappearance of Kit on day 28 fetal liver-derived mast cells is complete 3 days after exposure of the cells to SCF and is detectable by 2 days. Recovery requires new protein and new RNA synthesis, because Kit did not reappear if cycloheximide or actinomycin D was added to the cells. No substantial change in total Kit mRNA was detected during the resynthesis period, suggesting that post-transcriptional regulation of Kit production is involved. Internalization of Kit in mast cells exposed to soluble SCF may represent a negative regulatory mechanism for this receptor-ligand interaction and down-regulate mast cell properties such as degranulation to SCF.
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PMID:Internalization of Kit together with stem cell factor on human fetal liver-derived mast cells: new protein and RNA synthesis are required for reappearance of Kit. 861 71

Abnormal adhesive interaction between bone marrow stroma and progenitors, one of the causes of unregulated proliferation in chronic myelocytic leukaemia (CML), may be caused by some alterations in adhesion molecules on CML progenitors. We investigated the expression of adhesion molecules (CD44, VLA-5, VLA-4, LFA-1, ICAM-1, L-selectin and c-kit) on bone marrow CD34++ cells from 16 CML patients by three-colour flow cytometry. The mean percentage of cells expressing L-selectin in the CD34++CD38+(or)++ fraction from untreated CML patients was significantly lower, and that in the CD34++CD38- fraction tended to be lower than that from normal controls. Among 11 CML patients treated with interferon-alpha (IFN-alpha), the mean percentage of the cells expressing L-selectin in the CD34++CD38- fraction from three patients with a low percentage of Ph1(+) cells in bone marrow was significantly higher than that from five patients with a high percentage of Ph1(+) cells. In addition, L-selectin expression rate was inversely correlated to the percentage of Ph1(+) cells. There was no significant difference between the untreated patients and normal controls with regard to the expression rates of the other adhesion molecules in each CD34++ fraction except LFA-1. These data suggest that decreased L-selectin expression in CML CD34++ cells reflects one of the features of malignant CML progenitors.
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PMID:Decreased L-selectin expression in CD34-positive cells from patients with chronic myelocytic leukaemia. 863 30

Cytokines play a crucial role in the differentiation and proliferation of hemopoietic cells, and it has recently been found that adhesion molecules play crucial roles not only in differentiation and proliferation, but also in the homing and other functions of hemopoietic cells. We have very recently established a new method for purifying pluripotent hemopoietic stem cells (P-HSC) in mice by injecting 5-fluorouracil (5-FU). The P-HSC were found to be low-density, lineage marker-negative (Lin-), CD71- and major histocompatibility complex class I(high). In the present study, we analyze changes in the expression of various HSC markers (Sca-1 and CD34), receptors (c-kit and interleukin-6 receptor [IL-6R]) and adhesion molecules (very late activation antigen-4 [VLA-4], lymphocyte function-associated antigen-1 [LFA-1], and CD44) after 5-FU injection. The percentage of Sca-1+ cells increases after 5-FU treatment, reaching a maximum on day 3, whereas the percentage of IL-6R+ cells decreases, reaching a minimum on day 3. The percentage of CD34+ cells does not change after 5-FU treatment. The percentages of both c-kit(low) and c-kit(high) cells decrease, reaching a minimum on day 3 after 5-FU treatment, whereas the percentage of c-kit- cells reciprocally increases, reaching a maximum on day 3. However, there is no change in the expression of adhesion molecules (VLA-4, LFA-1 and CD44) on the P-HSC.
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PMID:Changes in markers, receptors and adhesion molecules expressed on murine hemopoietic stem cells after a single injection of 5-fluorouracil. 888 99

Comparative studies of the CD34+ cell population in peripheral blood (PB) and bone marrow (BM) may contribute to understanding the mechanisms involved in mobilization of hematopoietic progenitor cells (HPCs) from BM to PB. PB-CD34+ and BM-CD34+ cells in steady-state hematopoiesis and during granulocyte colony-stimulating factor (G-CSF) administration were studied for the expression of activation-associated, lineage-associated and adhesion-associated molecules and for their cloning capacity [granulocyte-macrophage colony-forming cells (CFU-GM) and burst-forming unit-erythrocytes (BFU-E)]. G-CSF increased significantly the number of CD34+ cells in PB as well as in BM and resulted in a reduction of CD34+ cells coexpressing the adhesion-related molecule CD49d. Further, G-CSF reduced the relative number of lymphoid progenitors (CD34+ cells coexpressing CD10, CD19, CD20, CD2, or CD7) in both compartments. However, G-CSF had no major impact on the observed differences between PB-CD34+ and BM-CD34+ cells seen during steady-state hematopoiesis despite a relative decrease in PB and increase in BM of certain immature progenitors (CD34+DR- cells). Circulating CD34+ cells, even in steady-state, were enriched for colony-forming cells, and individual colonies appeared larger compared with their BM counterparts. PB-CD34+ cells contained relatively more myeloid progenitors (CD34+CD13+ cells) and fewer B lymphoid progenitors (CD10, CD19, and CD20 cells) than BM-CD34+ cells. CD34+DR-cells were present in a higher proportion of the CD34+ cells in PB than in BM. There were lower numbers of CD34+ cells expressing CD49d and c-kit in PB than in BM. To summarize, the differences between PB-CD34+ and BM-CD34+ cells observed during steady-state hematopoiesis were largely conserved during G-CSF administration. G-CSF, therefore, mainly has an effect on the quantity not the composition of the circulating CD34+ cell pool. Our data also suggest that the egress of HPCs from BM during steady-state hematopoiesis, as well as during G-CSF administration, is a selective process; that is, certain subsets are more prone to enter into circulation than others, and this release may be mediated via common pathway possibly involving downregulation of c-kit and VLA-4 (CD49d).
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PMID:Efflux of CD34+ cells from bone marrow to peripheral blood is selective in steady-state hematopoiesis and during G-CSF administration. 948 91

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

We have previously demonstrated that PU.1 is required for the production of lymphoid and myeloid, but not of erythroid progenitors in the fetal liver. In this study, competitive reconstitution assays show that E14.5 PU.1(-/-) hematopoietic progenitors (HPC) fail to sustain definitive/adult erythropoiesis or to contribute to the lymphoid and myeloid lineages. PU.1(-/-) HPC are unable to respond synergistically to erythropoietin plus stem cell factor and have reduced expression of c-kit, which may explain the erythroid defect. Fluorescently labeled, PU.1(-/-), AA4.1(+), fetal liver HPC were transferred into irradiated recipients, where they demonstrated a severely impaired ability to home to and colonize the bone marrow. PU.1(-/-) HPC were found to lack integrins alpha(4) (VLA-4/CD49d), alpha(5) (VLA-5/CD49e), and CD11b (alpha(M)). Collectively, this study has shown that PU.1 plays an important role in controlling migration of hematopoietic progenitors to the bone marrow and the establishment of long-term multilineage hematopoiesis.
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PMID:A critical role for PU.1 in homing and long-term engraftment by hematopoietic stem cells in the bone marrow. 1043 16

The rate of reconstitution following hematopoietic stem cell (HSC) transplantation differs widely depending on the tissue source of the cells infused. To test the hypothesis that variability in engraftment kinetics is related to differences in the efficiency with which intravenously transplanted HSCs "home" to the bone marrow (BM), the homing properties of murine fetal liver (FL), adult BM, and mobilized peripheral blood (MPB) cells were compared. Lethally irradiated mice transplanted with 2 x 10(6) FL, BM, or MPB cells exhibited sequentially slower recovery of circulating leukocytes and platelets that correlates with the progressively lower frequency of colony-forming cells (CFCs) in these tissues. However, differences in the rate and degree of early and long-term reconstitution were maintained even after infusing equal numbers of CFCs derived from FL, BM, and MPB. To compare the homing of progenitors from these tissues, cells were labeled with fluorescent PKH26 dye and injected into lethally irradiated hosts. Three hours later, PKH26(+) cells were reisolated from the BM and spleen by fluorescence-activated cell sorting and assayed for in vitro CFCs. Despite the higher level of very late antigen (VLA)-2, VLA-4, and VLA-5 on Sca-1(+)c-kit(+) cells from FL compared to BM, 10-fold fewer FL CFCs homed to hematopoietic organs than those from BM. MPB cells homed slightly better, but still less efficiently than BM cells. Therefore, clonogenic cells from different tissues exhibit striking variations in homing efficiency that does not necessarily correlate with engraftment kinetics. Homing is likely counterbalanced by intrinsic differences in proliferative potential that ultimately determine the rate of hematopoietic reconstitution.
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PMID:Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. 1156 97

Bone marrow stromal cell lines (TBR cell lines) established from temperature-sensitive Simian Virus 40 T-antigen gene transgenic mice exhibited myogenic, osteogenic, and adipogenic differentiation. The effect of oncostatin M (OSM) on such mesenchymal cell differentiation of marrow stromal cell lines was examined. One of those stromal cell lines, TBRB, differentiated into skeletal muscle, and its differentiation was stimulated by OSM, whereas differentiation of TBR10-1 into smooth muscle was inhibited by OSM. TBR31-2 is a bipotent progenitor for adipocytes and osteoblasts, and OSM stimulated osteogenic differentiation while inhibiting adipogenic differentiation. On the other hand, TBR cell lines exhibited various potentials for supporting hematopoiesis in culture. When hematopoietic progenitor cells were cocultured with OSM-stimulated stromal cell lines, TBR10-1 and TBR31-2 exhibited enhanced hematopoietic supportive activity. As responsible molecules for stromal cell dependent hematopoiesis, expression of stem cell factor (SCF) (a ligand of c-Kit), vascular cell adhesion molecule (VCAM-1) (a ligand of VLA-4), and secretion of interleukin (IL)-6 were increased by OSM. OSM affected mesenchymal cell differentiation and promoted the hematopoietic supportive activity of marrow stromal cell lines. As OSM production is induced by cytokines from hematopoietic cells, OSM may be a key factor in mutual regulation between hematopoietic cells and stromal cells in the bone marrow. OSM may play a role as a regulator in maintaining the hematopoietic microenvironment in marrow by coordinating mesenchymal differentiation.
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PMID:Oncostatin m regulates mesenchymal cell differentiation and enhances hematopoietic supportive activity of bone marrow stromal cell lines. 1177 76

Adhesion to extracellular matrix plays important roles in the regulation of survival, proliferation, differentiation and homing of hematopoietic cells and is regulated by a wide variety of growth factors, adhesion receptors and other ligands that mediate the cell to matrix and cell to cell interaction. Stem cell factor (SCF) plays important roles in the regulating growth and self-renewal of hematopoietic stem/progenitor cells. In the report, the effects of stem cell factor on the adhesion of hematopoietic cells to fibronectin were observed by using a hematopoietic growth factor dependent cell line-Mo7e. Results showed that Mo7e cells express the very late antigen VLA-4 (beta1 alpha4) and VLA-5 (beta1 alpha5) integrins. The expression of the SCF receptor (c-kit) was also detected in the Mo7e cells. SCF enhances the adhesion of Mo7e cells to fibronectin in a concentration dependent manner. SCF enhanced adhesion of Mo7e cells to fibronectin was blocked by anti-beta1, alpha4 and alpha5 antibodies. Addition of PI-3 kinase inhibitors also blocked the adhesion of Mo7e cells to fibronectin induced by SCF. It was concluded that SCF enhances the adhesion of Mo7e cells to fibronectin, and this process is mediated by integrins and PI-3 kinase pathway.
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PMID:[Stem cell factor enhances the adhesion of hematopoietic cells to fibronectin]. 1251 5


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