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)

Proliferating populations of neutrophils, monocytes, eosinophils, erythroid cells, and T-lymphocytes from normal subjects or patients with various diseases can now be analysed by colony formation in semisolid cultures. These cultures accurately determine the number and proliferative activity of the precursor cells of each population and can also be used to monitor the levels of specific regulatory factors (for example, erythropoietin, colony-stimulating factor) in the serum or urine of such patients. Studies using semisolid cultures have shown that the leukemic cells in chronic and acute myeloid leukemia remain dependent on the normal regulator, granulocyte-macrophage colony-stimulating factor, for proliferation. The cultures have proved valuable in the prognostic assessment of acute leukemic patients and in monitoring impending changes in the clinical status of patients with acute or chronic myeloid leukemia or myeloproliferative disorders.
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PMID:In-vitro cloning techniques for hemopoietic cells: clinical applications. 33 9

The murine myeloproliferative syndrome induced by the myeloproliferative sarcoma virus (MPSV) has numerous similarities to human primary myelofibrosis. We have shown that medium conditioned by spleen cells of MPSV-infected mice has the capacity to support the growth of primitive blast cell colonies. The detection of this activity associated with MPSV infection stimulated us to characterize the hematopoietins responsible for this activity. Northern blot analysis showed a large increase, or induction, of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-CSF (CSF-1), and granulocyte-CSF (G-CSF) transcripts in the hematopoietic organs of MPSV-infected mice; however, no IL-3 transcript could be detected in either MPSV-infected or normal mice. Significant levels of IL-1 alpha, IL-6, G-CSF, and CSF-1 bioactivities were found in the serum of MPSV-infected mice, but not in controls. Additionally, analysis of medium conditioned by spleen cells of MPSV-infected mice showed the presence of tumor necrosis factor alpha bioactivity. The increased production of cytokines that are able to stimulate pluripotent hematopoietic stem cells corroborates the hypothesis of a possible involvement of hematopoietic growth factors in the development of some myeloproliferative disorders.
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PMID:Enhanced hematopoietic growth factor production in an experimental myeloproliferative syndrome. 137 44

Chronic granulocytic leukemia is a rare myeloproliferative disorder in dogs. The present study investigated various functions of leukemic granulocytes in a dog that presented with thrombocytopenic purpura, anaemia and a classical leukemic hemogram. All analyses were performed in parallel with a control dog. Purification of the leukemic granulocytes by density gradient centrifugation revealed three neutrophil and neutrophil precursor populations with different densities. Comparison of cell morphology and density showed that cell density increased with increasing maturity. The control dog possessed only one neutrophil population, with a density greater than 1.077. Analysis of cellular contents of the granular enzymes, elastase, myeloperoxidase and lysozyme showed that leukemic neutrophils were quantitatively markedly different from normal neutrophils with respect to enzyme activities. There were no major differences between leukemic and normal cells as regards aggregatory and migratory responses to different stimuli. The phagocytic capacity of the leukemic cells, however, was dramatically increased compared with the control, and exceeded all previously encountered responses in the assay employed. In a similar fashion, superoxide generation and secretion of elastase and lysozyme in response to zymosan and phorbol myristate acetate were substantially higher than in the control dog. Priming of cell function to a level exceeding that normally attainable in neutrophils appears to have taken place in peripheral blood of the leukemic dog. The only endogenous mediator known to prime neutrophil functions to the extent seen in the present case is the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which is intimately involved in regulation of myelopoiesis in mammals. On the basis of the enzymological and functional findings in the leukemic dog, we hypothesize that a lactoferrin deficiency in leukemic neutrophils leads to enhanced GM-CSF synthesis, which is ultimately the cause of the observed cellular hyperresponsiveness and contributes to the monocytosis seen in the patient.
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PMID:Enhanced granulocyte function in a case of chronic granulocytic leukemia in a dog. 165 Oct 30

Interferons (IFNs) have been shown to suppress the proliferation of human pluripotent and single-lineage hematopoietic progenitor cells. Treatments with IFNs have reduced platelet counts in patients with myeloproliferative disorders (MPD) but have not altered platelet counts in patients with healthy marrows. We assessed recombinant alpha and gamma IFN (rIFN-alpha and rIFN-gamma) preparations for their effect on the growth of marrow megakaryocytes (MKs) from normal donors and from patients with MPD. In addition, the interactions of recombinant interleukin 3 (rIL-3) recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM) with the suppressive effects of rIFNs were examined. The addition of rIFN-alpha to liquid cultures resulted in a dose-dependent inhibition of normal marrow and MPD marrow MK growth. Inhibition with rIFN-gamma was only observed in normal marrows at 2500 U/ml and 12,500 U/ml; and rIFN-gamma unexpectedly stimulated MK growth in some culture conditions. Thirty units per milliliter rIL-3 overcame the inhibitory effect of rIFN-alpha on MK growth, but rGM-CSF or 3 U/ml rIL-3 did not. These studies with rIFN-alpha demonstrate that MPD marrow MKs and their precursor cells are no more sensitive to rIFN-alpha than are normal marrow MKs. Clinically, rIFN-gamma would be expected to be less effective than rIFN-alpha at controlling thrombocytosis in patients with MPD.
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PMID:Effects of recombinant interferons on human megakaryocyte growth. 211 55

A male neonate with Down's syndrome and congenital myeloproliferative disorder was studied. His blood picture showed the unique coexistence of leukocytosis with matured cells and a large number of blast cells. The in vitro proliferation and differentiation of blast cells into various lineages in the presence of phytohemagglutinin-stimulated leukocyte conditioned medium (PHA-LCM) was examined by using a liquid culture and a methylcellulose culture system. The differentiation of blast cells into myeloid cells was confirmed by specific cytochemical stainings, electron microscopy, and an immunologic study. No specific factors in the plasma of the patient promoted the proliferation or differentiation of blast cells. The cellular composition of colonies grown in methylcellulose culture from single blast cells was studied by a micromanipulation technique. High plating efficiency was observed. Of 136 cultures, 78 showed colony growth. Half of the blast cells were colony-forming cells that could proliferate and differentiate into basophils, neutrophils, eosinophils, macrophages, and erythrocytes in the presence of PHA-LCM. Using the blast cells with a high differentiation capacity to the basophil pathway, we studied the effect of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF). Recombinant GM-CSF support neutrophils, eosinophils, and macrophages but not typical basophils. These findings of the cell differentiation of blast cells into various kinds of cells in vitro were in agreement with the finding of neutrophilia, eosinophilia, basophilia, and thrombocythemia in this patient.
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PMID:Differentiation of blast cells from a Down's syndrome patient with transient myeloproliferative disorder. 294 80

Myelodysplastic syndromes (MDS) are clonal disorders of the multipotent hematopoietic stem cell characterized by ineffective hematopoiesis and associated with marrow hypercellularity, increased intramedullary cell death and peripheral cytopenias of varying severity. Patients with myelodysplasia have a propensity (20% to 30% of cases) to undergo transformation into acute myeloid leukemia (AML), and a large body of evidence indicates that MDS represent steps in the multiphasic evolution of AML. Progression of the disease is characterized by expansion of the abnormal clone and inhibition of normal hematopoiesis leading to deterioration of the blood cell count and/or development of AML. MDS are relatively unusual in childhood, representing only 3% of pediatric hematological malignancies, although it has been reported that up to 17% of pediatric AML cases may have a previous myelodysplastic phase. The first systematic attempt at morphological classification of MDS was provided by the French-American-British (FAB) group. However, the FAB classification of MDS is only partially applicable in children. Some variants are extremely rare or absent (refractory anemia with ring sideroblasts and chronic myelomonocytic leukemia), and other peculiar pediatric disorders, represented by juvenile chronic myelogenous leukemia (JCML) and the monosomy 7 syndrome, are not included. Moreover, since there is a partial overlap between pediatric MDS and myeloproliferative disorders and the variants occurring in young children have rather specific features, some confusion still surrounds the nosographical definition of childhood MDS, so that none of the proposed classifications are widely accepted and used. Characteristically, some genetic conditions such as Fanconi's anemia, Shwachman's and Down's syndromes predispose to the development of MDS in childhood. The most common variants of childhood MDS are represented by JCML and the monosomy 7 syndrome, both disorders typically occurring in young children. JCML is characterized by a spontaneous growth of granulocyte-macrophage progenitors that show a striking hypersensitivity to granulocyte-macrophage colony-stimulating factor. Clinical presentation resembles that of some myeloproliferative disorders, with massive organomegaly usually not observed in the classically reported variants of MDS. Clinical features of the monosomy 7 syndrome resemble those observed in JCML and a differential diagnosis between these two entities relies upon the higher percentage of fetal hemoglobin, the more pronounced decrease in platelet count and, in some cases, the lack of the peculiar cytogenetic abnormality in the latter. With the number of children being cured of cancer constantly rising, a significant increase in secondary or chemotherapy-related myelodysplasia is being observed, and these disorders represent a formidable challenge for pediatric hematologists due to their poor response to chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Myelodysplastic syndromes: the pediatric point of view. 767 22

The bcr-abl oncogene plays a critical role in causing chronic myelogenous leukemia (CML). Effective laboratory animal models of CML are needed to study the molecular mechanisms by which the bcr-abl oncogene acts in the disease progression of CML. We used a murine stem cell retroviral vector (MSCV) to transduce the bcr-abl/p210 oncogene into mouse bone marrow cells and found that expression of Bcr-Abl/p210 induced a myeloproliferative disorder that resembled the chronic phase of human CML in 100% of bone marrow transplanted mice in about 3 weeks. This CML-like disease was readily transplanted to secondary recipient mice. Multiple clones of infected cells were expanded in the primary recipients, but the leukemia was primarily monoclonal in the secondary recipient mice. Mutation analysis demonstrated that the protein tyrosine kinase activity of Bcr-Abl/p210 was essential for its leukemogenic potential in vivo. Interestingly, we found that the leukemic cells expressed excess interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the diseased mice. These studies demonstrate that expression of Bcr-Abl can induce a CML-like leukemia in mice much more efficiently and reproducibly than in previously reported mouse CML models, probably due to efficient expression in the correct target cell(s). Our first use of this model for analysis of the molecular mechanisms involved in CML raises the possibility that excess expression of hematopoietic growth factors such as IL-3 and GM-CSF may contribute to the clinical phenotype of CML.
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PMID:Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia. 980 76

Oncogenic RAS alleles encode proteins that accumulate in the guanosine triphosphate (GTP)-bound state. Because post-translational processing of Ras by farnesyltransferase is essential for biologic function, inhibitors of this enzyme have been developed as rational cancer therapeutics. We have investigated farnesyltransferase inhibitor (FTI) L-744,832 in an in vivo murine model of myeloid leukemia that is associated with inactivation of the Nf1 tumor suppressor gene. Nf1 encodes a GTPase activating protein for Ras, and Nf1-deficient (Nf1-/-) hematopoietic cells show hyperactive Ras signaling through the mitogen-activated protein (MAP) kinase pathway. L-744,832 inhibited H-Ras prenylation in cell lines and in primary hematopoietic cells and abrogated the in vitro growth of myeloid progenitor colonies in response to granulocyte-macrophage colony-stimulating factor (GM-CSF). This FTI also partially blocked GM-CSF-induced MAP kinase activation, but did not reduce constitutively elevated levels of MAP kinase activity in primary Nf1-/- cells. Injection of a single dose of 40 or 80 mg/kg of L-744, 832 increased the amount of unprocessed H-Ras in bone marrow cells, but had no detectable effect on N-Ras. Adoptive transfer of Nf1-/- hematopoietic cells into irradiated mice induces a myeloproliferative disorder that did not respond to L-744,832 treatment. We speculate that the lack of efficacy in this model is due to the resistance of N-Ras and K-Ras processing to inhibition by this FTI.
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PMID:In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells. 1049 20

The NF1 tumor suppressor gene encodes neurofibromin, a GTPase-activating protein (GAP) for p21ras (Ras). Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML). Some heterozygous Nf1 mutant mice develop a similar myeloproliferative disorder (MPD), and adoptive transfer of Nf1-deficient fetal liver cells consistently induces this MPD. Human JMML and murine Nf1-deficient cells are hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) in methylcellulose cultures. We generated hematopoietic cells deficient in both Nf1 and Gmcsf to test whether GM-CSF is required to drive excessive proliferation of Nf1-/- cells in vivo. Here we show that GM-CSF play a central role in establishing and maintaining the MPD and that recipients engrafted with Nf1-/- Gmcsf-/- hematopoietic cells are hypersensitive to exogenous GM-CSF.
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PMID:Nf1 and Gmcsf interact in myeloid leukemogenesis. 1067 81

Tyrosine kinase fusion oncogenes that occur as a result of chromosomal translocations have been shown to activate proliferative and antiapoptotic pathways in leukemic cells, but the importance of autocrine and paracrine expression of hematopoietic cytokines in leukemia pathogenesis is not understood. Evidence that leukemic transformation may be, at least in part, cytokine dependent includes data from primary human leukemia cells, cell culture experiments, and murine models of leukemia. This report demonstrates that interleukin (IL)-3 plasma levels are elevated in myeloproliferative disease (MPD) caused by the TEL/tyrosine kinase fusions TEL/platelet-derived growth factor beta receptor (PDGFbetaR), TEL/Janus kinase 2 (JAK2), and TEL/neurotrophin-3 receptor (TRKC). Plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were elevated by TEL/PDGFbetaR and TEL/JAK2. However, all of the fusions tested efficiently induced MPD in mice genetically deficient for both GM-CSF and IL-3, demonstrating that these cytokines are not necessary for the development of disease in this model system. Furthermore, in experiments using normal marrow transduced with TEL/PDGFbetaR retrovirus mixed with marrow transduced with an enhanced green fluorescent protein (EGFP) retrovirus, the MPD induced in these mice demonstrated minimal stimulation of normal myelopoiesis by the TEL/PDGFbetaR-expressing cells. In contrast, recipients of mixed GM-CSF-transduced and EGFP-transduced marrow exhibited significant paracrine expansion of EGFP-expressing cells. Collectively, these data demonstrate that, although cytokine levels are elevated in murine bone marrow transplant models of leukemia using tyrosine kinase fusion oncogenes, GM-CSF and IL-3 are not required for myeloproliferation by any of the oncogenes tested.
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PMID:Induction of myeloproliferative disease in mice by tyrosine kinase fusion oncogenes does not require granulocyte-macrophage colony-stimulating factor or interleukin-3. 1122 91


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