Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral blood cells from a female patient with Ph1-positive chronic myelogenous leukemia (CML) in blast crisis were serially transplanted in BALB/c nude mice for 16 passages. This in vivo cell line, designated CML-N-1, had Ph1 chromosome abnormality and BCR gene rearrangement. The cells expressed CD11b, CD13, CD33, CD34, CD38, and HLA-DR antigens until the 11th passage and subcutaneous tumors produced by these passages were composed of admixtures of immature and maturing cells that differentiated to basophils when cultured in vitro. From the 12th passage on, the tumors became composed mainly of immature cells expressing CD13, CD34, and HLA-DR, and no longer differentiated to basophils even upon in vitro culture. In contrast to the vigorous proliferation in vivo, CML-N-1 cells from any passage failed to proliferate in vitro under standard liquid culture conditions with or without growth factors, such as granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, monocyte colony-stimulating factor, interleukin 3, interleukin 6 and stem cell factor. However, a continuously growing cell line, designated CML-C-1, was established by culturing CML-N-1 cells on feeder layers of mouse bone marrow stromal cells. This mouse bone marrow stromal cell-dependent cell line showed immature cell morphology and expressed early myeloid phenotype positive for CD13, CD34, and HLA-DR. These results indicate that mouse bone marrow stromal cells provide a certain growth factor(s) active on human leukemia cells.
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PMID:Direct transplantation of chronic myelogenous leukemia cells into nude mice and establishment of a leukemic stem cell (Ph1+, CD34+) line dependent on mouse bone marrow stromal cells in vitro. 754 Jun 8

Thrombopoietin (TPO) is a newly identified hematopoietic growth factor that stimulates both megakaryopoiesis and thrombopoiesis through its interaction with a specific cell surface receptor encoded by the c-mpl proto-oncogene. In an effort to investigate the effect of TPO on human myeloid leukemia cells, the expression of c-mpl and the proliferative response to recombinant human (rh) TPO were investigated in a series of patients with acute myeloblastic leukemia (AML). Of 50 cases of AML, the c-mpl mRNA was detectable by means of Northern blot analysis in 26 cases, and the in vitro treatment with rhTPO led to proliferation of AML cells in 22 cases. The c-mpl expression and proliferative response to rhTPO was observed in all subtypes of AML and did not correlate with French-American-British classification, whereas all cases of M7-type AML cells expressed c-mpl and proliferated in response to rhTPO. Furthermore, rhTPO-induced proliferation of AML cells was augmented with the addition of interleukin-3 (IL-3), IL-6, stem cell factor, or granulocyte-macrophage colony-stimulating factor. These results suggested that c-mpl may be functional in terms of supporting proliferation of various types of AML cells and that TPO may contribute, at least in part, to abnormal growth of the cells, especially in combination with other hematopoietic growth factors.
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PMID:Growth response of acute myeloblastic leukemia cells to recombinant human thrombopoietin. 754 72

The effect of basic fibroblast growth factor (bFGF) alone and in combination with other hematopoietic growth factors on the colony formation of K562 human leukemic cells was studied using soft agar colony assay. bFGF was found to have a weak colony-stimulating activity on K562 cells derived from the blastic crisis cells of human chronic myelogenous leukemia and to potentiate the K562 cell colony-stimulating activity of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and stem cell factor (SCF) at a low concentration of below 1 ng/ml. These findings suggested that bFGF stimulates the growth of human leukemic cells directly in vivo alone and in synergy with other hematopoietic growth factors.
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PMID:Synergistic effects of basic fibroblast growth factor and hematopoietic growth factors on colony formation of K562 human leukemic cells. 754 54

Multilineage colony formation was evaluated from healthy donors' bone marrow (BM), peripheral blood (PB) and cord blood (CB) and compared with blood stem cell (BSC) harvests of sarcoma patients mobilized with granulocyte-macrophage colony-stimulating factor (GM-CSF). The test was a modified CFU-blast assay performed with and without an irradiated foetal mesenchymal cell layer (HFFF). These non-transformed mesenchymal cells served as a good source of haematopoietically active stroma cells in that cytokine expression patterns (interleukin (IL)-6, granulocyte (G)-CSF, GM-CSF) and adhesion molecules on HFFF cells were qualitatively identical to BM-derived fibroblasts, but the expression density of adhesion receptors was significantly higher. This HFFF layer stimulated blood stem cells of GM-CSF-treated patients significantly more than a cocktail of exogenous growth factors with IL-1, IL-6, and stem cell factor (SCF). The reverse was true for multilineage colonies from healthy donors' PB, BM, and CB. According to these results, stem cells of GM-CSF-treated patients are functionally distinct due to their dependence on stroma-derived factors and/or matrix-adhesion interactions and can be reproducibly evaluated on these mesenchymal cells.
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PMID:Mixed haematopoietic colony formation via immature blast cell clusters on foetal mesenchymal cell layers distinguishes stem cells from peripheral blood, cord blood, bone marrow and blood stem cells mobilized by granulocyte-macrophage colony-stimulating factor. 754 89

A new and quantitative liquid culture system has been developed to measure the production of megakaryocytes from megakaryocyte progenitor cells (colony-forming units-megakaryocyte [CFU-MK]). The system uses as a target population a glycoprotein (Gp) IIb/IIIa+ subpopulation of rat bone marrow cells previously demonstrated to be highly enriched for CFU-MK. GpIIb/IIIa+ cells were cultured at 5 x 10(4) cells/mL (10(4) cells/well) with test samples in 96-well tissue culture plates for 4 days at 37 degrees C. During the final 3 hours of incubation, the cells were pulsed with [14C]5-hydroxytryptamine creatinine sulfate (14C-serotonin). After incubation, the plates were washed and the cell pellets were lysed with Triton-X 100. The cell lysate was infiltrated into a commercially available solid scintillator and dried, and radioactivity was measured. In this assay system, rat interleukin-3 (IL-3) was found to be the most potent among known cytokines tested. Murine granulocyte-macrophage colony-stimulating factor (GM-CSF), human erythropoietin (Epo), human IL-6, and murine stem cell factor (SCF) each alone stimulated megakaryocyte growth but were much less active than rat IL-3. Plasma of rats rendered thrombocytopenic by injection of monoclonal antirat platelet GpIIb/IIIa antibody exhibited significant activity, and the active protein fractions partially purified from the plasma showed much higher activity, but normal rat plasma had no effect. This liquid culture system allows the measurement of a large number of test samples--including a wide variety of cytokines and unknown growth factors, alone or in combinations--and provides a simple method for evaluating the early proliferative events involving CFU-MK in the megakaryocyte differentiation pathway.
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PMID:A simple and quantitative liquid culture system to measure megakaryocyte growth using highly purified CFU-MK. 755 34

Expression of major histocompatibility complex (MHC) class II molecules is developmentally regulated and lineage dependent. Their role in hematopoiesis is not well defined. Previous studies in a canine model showed that dogs given 920 cGy of total body irradiation, transplanted with autologous marrow, and treated with anti-MHC class II monoclonal antibody (MoAb) immediately posttransplant experienced only a transient granulocyte recovery that was followed by graft failure. In the present study, the effect of anti-MHC class II MoAbs on canine in vitro hematopoiesis was investigated. Anti-MHC class II MoAb H81.9 or B1F6 (both recognizing nonpolymorphic determinants) had no inhibitory effect when added directly to colony-forming unit-granulocyte-macrophage (CFU-GM) grown in agar. However, the addition of intact MoAb or as F(ab')2 fragments to long-term marrow cultures (LTMCs) resulted in a dose-dependent inhibition of the generation of CFU-GM among nonadherent cells. Inhibition was most profound with MoAb added at the time of initiation of culture. However, even if MoAb was added 3 weeks after recharging LTMCs, CFU-GM generation rapidly decreased. In addition, the number of adherent cells in LTMCs decreased; predominantly fibroblast-like cells with prominent cytoplasmic vesiculation remained. Acridine orange/ethidium bromide staining and TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) tests showed an increase in the proportion of apoptotic cells in both the nonadherent and adherent compartments. Binding of anti-MHC class II MoAb to unfractionated marrow cells resulted in an increase in free (Ca2+)i; no changes in tyrosine phosphorylation pattern were observed. The addition of stem cell factor (SCF), but not granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, to LTMCs prevented apoptosis, and the generation of CFU-GM was indistinguishable from controls. Similarly, a supportive adherent layer was maintained. Thus, anti-MHC class II MoAbs interfere with hematopoiesis both in vitro and in vivo. The mechanism involves programmed cell death in subpopulations of adherent and nonadherent cells. Inhibition of hematopoiesis is abrogated by exogenous SCF.
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PMID:Major histocompatibility complex class II-mediated inhibition of hematopoiesis in long-term marrow cultures involves apoptosis and is prevented by c-kit ligand. 861 36

Perfusion cultures of human bone marrow mononuclear cells (BMMNC) provide a unique in vitro model of hematopoiesis, supporting growth of both accessory and hematopoietic elements. In this study, bioreactors were used to analyze the consumption and production of growth factors (GFs) in relation to each other and to the cells produced. The exogenously added GFs interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), and erythropoietin (Epo) each exhibited different, but reproducible, consumption kinetics. Epo and IL-3 were consumed slowly for the first 5-7 days, and then the consumption rate of both increased. Epo consumption reached a plateau by day 10, whereas IL-3 consumption continued to increase. Consumption of SCF was similar to that of Epo, but began 2-3 days earlier. GM-CSF was consumed throughout the culture period in an accelerating manner. Consumption of SCF and Epo were related, because omission of Epo from the growth medium reduced SCF consumption by 53% and omission of SCF reduced Epo consumption by 82%. A reproducible relationship between cumulative GF consumption and total cell production was observed. Epo was most potent, with 5900 molecules consumed per cell produced, whereas 69,400 molecules of SCF were consumed per cell generated. More specifically, Epo consumption was correlated (r = 0.92 and 0.96) with the number of glycophorin A-positive (glyA+) cells produced, and the rate of Epo consumption varied with the progression of cells through the erythroid lineage. Consequently, measurement of GF consumption rates may be useful for quantifying the types of cells present in a culture. Endogenous GF production was also examined. G-CSF and MIP-1 alpha were present at high levels during the first 4 days but then declined rapidly. LIF first appeared in the second week and steadily increased thereafter. Omission of SCF from the medium allowed the detection of endogenous SCF production, and the kinetics was similar to that of LIF. IL-6 production was biphasic, with a peak and decline in week 1 and an increase during week 2. TGF-beta was below the level of detection in these cultures. The results suggest that perfusion supports accessory and hematopoietic elements which interact and therefore represent a partially functional tissue ex vivo. This system provides a useful model for studying relationships within GF networks and for elucidating the conditions that result in primitive cell expansion ex vivo.
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PMID:Growth factor consumption and production in perfusion cultures of human bone marrow correlate with specific cell production. 758 82

We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen-4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor-alpha, transforming growth factor-beta 1, or transforming growth factor-beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts.
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PMID:Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand. 763 39

Hemopoietic stem cells adhere to hemopoietic supportive (MS-5) cells, but not to non-supportive (MS-K) cells. Although a soluble stem cell factor (SCF) was produced by both of these cell lines, little activity was detectable in the supernatant from the cultures of either of these cells, indicating that SCF might be compartmentalized within the extracellular matrix (ECM), and transferred directly to the stem cells via the ECM (44). To probe this possibility, we studied the transfer of SCF from the ECM and the subsequent support of the survival of the hemopoietic stem cells. A stem cell-enriched bone marrow cell fraction was overlaid on SCF-containing ECM. The stem cells survived and proliferated for some days without differentiation under these conditions, whereas stem cells overlaid on ECM without SCF died within a few days. Addition of interleukin-3 (IL-3) to the ECM that contains SCF, induced differentiation of the stem cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced further differentiation of the stem cells, which was accompanied by a decrease in the number of colony-forming unit in spleen (CFU-S). These observations verified the above hypothesis, and indicated that the survival, the self-renewal, and the differentiation of hemopoietic stem cells can be separately controlled at least in vitro.
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PMID:Separate control of the survival, the self-renewal and the differentiation of hemopoietic stem cells. 764 Dec 93

Leukemic cells from a patient with chronic myelocytic leukemia (CML) basophilic crisis were examined in an in vitro clonogenic assay using recombinant human hematopoietic growth factors to elucidate the proliferative and differentiative behaviors. More than 90% of the leukemic cells showed the morphologic characteristics of basophils and were positive for CD11b and CD13. The phenotype of the leukemic cells was different from that of mast cells. In the clonogenic assay using various recombinant growth factors, the leukemic cells were responsive to interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), but not to granulocyte-CSF (G-CSF), erythropoietin (Epo), or IL-4. IL-5 showed synergistic effects on colony formations induced by both IL-3 and GM-CSF. Transcripts of the GM-CSF receptor alpha chain gene were detected in the leukemic cells, but transcripts of the IL-4 receptor gene were not. Furthermore, c-kit and IL-7 receptor genes were expressed in the leukemic cells. Our results suggest that the differentiation pathway of basophils is different from that of mast cells, even though the receptor gene for stem cell factor (c-kit) was expressed on the basophilic leukemic cells, as it was on mast cells.
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PMID:Cellular characteristics of chronic myelocytic leukemia basophilic crisis cells: phenotype, responsiveness to and receptor gene expression for various kinds of growth factors and cytokines. 767 84


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