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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukaemia (AML) blast cells express haemopoietic growth factor receptors. However, their presence does not predict response to the cognate ligand in vitro. This suggests that haemopoietic growth factor receptor structure or function may be abnormal in some cases of acute myeloid leukaemia. The granulocyte-macrophage colony-stimulating factor receptor alpha-chain gene (GM-CSF-R) has recently been localised to the pseudoautosomal region of the sex chromosomes. A sex chromosome is lost in 25% of cases of AML FAB subtype M2. The loss of one allele of this gene may have some aetiological significance in AML if the other allele is altered leading to abnormal receptor structure, function or number. In this initial study, we have examined DNA from leukaemic cells of 29 patients with AML, including three with FAB subtype M2 with deletion of an X or Y chromosome for evidence of gross rearrangement of this gene. We report that although the gene is highly polymorphic for a number of restriction enzymes, we have found no evidence of gross rearrangement in AML.
Leukemia 1992 Sep
PMID:Human GM-CSF receptor alpha-chain gene is highly polymorphic but not rearranged in AML. 138 92

The treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with high dose cytosine arabinoside (ara-C) results in short-lived complete response rates of 30-50%. We have previously shown that entry of myeloid leukemic cells into S phase can be accelerated in vitro through the use of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), resulting in enhancement of ara-C-mediated cytotoxicity. In order to evaluate the in vivo biological and clinical effects of this strategy in patients with high risk AML, we treated three patients with either refractory or relapsed disease with a continuous infusion of rhGM-CSF (0.45 micrograms/kg/h aglycoprotein) for 18 h, followed by the institution of high dose ara-C and continuation of rhGM-CSF throughout the 4 day duration of ara-C treatment. Prior to therapy, no patient had detectable levels of circulating rhGM-CSF, and there was no evidence of GM-CSF receptor occupancy in leukemic myeloblasts. After 18 h of rhGM-CSF therapy, all patients had biologically active levels of circulating rhGM-CSF (7.9-12.0 ng/ml), and two patients showed a significant degree of leukemic GM-CSF receptor occupancy without evidence of GM-CSF receptor down-regulation. A significant rise in the S phase fraction of leukemic myeloblasts was observed at 18 h of rhGM-CSF treatment in all three patients (29-56% increment). The toxicity of combined rhGM-CSF/ara-C therapy included pericarditis and cerebellar degeneration in one patient, fever and mild renal dysfunction in two patients, and mild hepatic dysfunction in all three patients. Each patient showed a transient rise in the absolute neutrophil and blast count during rhGM-CSF/ara-C administration, followed by profound, but clinically tolerable, myelosuppression. No patient developed clinical evidence of leukostasis. There was one death related to pericardial tamponade, one death related to refractory disease, and one clinical and cytogenetic remission. These results suggest that exogenously administered rhGM-CSF is capable of rapidly mobilizing leukemic cells into S phase in vivo and theoretically should be useful in overcoming kinetic resistance to ara-C. Clinical trials of this regimen in patients with high risk AML who are not already pharmacologically resistant to ara-C are warranted.
Leukemia 1991 Mar
PMID:Simultaneous administration of granulocyte-macrophage colony-stimulating factor and cytosine arabinoside for the treatment of relapsed acute myeloid leukemia. 182 36

The receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the surfaces of normal and leukemic myeloid cells were characterized using 125I-labeled bacterially synthesized GM-CSF. The binding was rapid, specific, time dependent, and saturable. Scatchard analysis of the 125I-GM-CSF binding to peripheral blood neutrophils indicated the presence of a single class of binding site (Kd = 99 +/- 21 pM; 2,304 +/- 953 sites/cell). However, for peripheral blood monocytes and two GM-CSF-responsive myeloid cell lines (U-937 and TF-1), the Scatchard plots were biphasic curvilinear, which were best fit by curves derived from two binding site model: one with high affinity (Kd1 = 10-40 pM) and the other with low affinity (Kd2 = 0.9-2.0 nM). For U-937 cells, the number of high-affinity receptors was 1,058 +/- 402 sites/cell and that of low-affinity receptors was estimated to be 10,834 +/- 2,396 sites/cell. Cross-linking studies yielded three major bands with molecular masses of 150 kDa, 115 kDa, and 95 kDa, which were displaced by an excess amount of unlabeled GM-CSF, suggesting 135-kDa, 100-kDa, and 80-kDa species for the individual components of the human GM-CSF receptor. These bands comigrated for different cell types including peripheral blood neutrophils, U-937 cells and TF-1 cells. In experiments using U-937 cells, only the latter two bands appeared to be labeled in a dose-dependent manner in a low-affinity state. These results suggest that the human GM-CSF receptor possibly forms a multichain complex.
Leukemia 1990 Jan
PMID:Characterization and molecular features of the cell surface receptor for human granulocyte-macrophage colony-stimulating factor. 215 63

The myeloproliferative leukemia virus (MPLV) is an acute leukemogenic murine replication-defective retrovirus. By sequencing the envelope gene of a biologically active MPLV clone, we found that this region comprises a novel oncogene named v-mpl in phase with two parts of the Friend murine leukemia virus envelope gene. The MPLV env region could encode an env-mpl fusion polypeptide that presents the characteristics of a transmembrane protein. We show that in vitro infection of bone marrow cells with helper-free MPLV readily yields immortalized factor-independent hematopoietic cell lines of different lineages. In mice, the c-mpl proto-oncogene is expressed in hematopoietic tissues as a 3 kb mRNA. Since v-mpl shares strong structural analogies with the hematopoietin receptor superfamily, it is likely that MPLV has transduced a truncated form of an as yet unidentified hematopoietic growth factor receptor.
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PMID:A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. 217 77

Equilibrium binding of 125I-labeled recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) to the blast cells of acute myeloblastic leukemia (AML) revealed the presence of two classes of binding components of high and low affinity, with dissociation constants (Kd) in the range of 5-10 pM and 1-10 nM, respectively. Specificity studies revealed that interleukin-3 (IL-3) could partially inhibit the binding of GM-CSF to AML blasts and to the cells of the leukemic lines M07-E, KG-1, and HL-60. The inhibition of GM-CSF binding by IL-3 was directly dependent on the presence of IL-3 receptors. Analysis of competition curves indicated that the Kd and the number of binding sites per cell of unlabeled and iodinated GM-CSF were identical. In contrast, the inhibition of GM-CSF binding by IL-3 was mediated by IL-3 occupancy of a high affinity receptor only, with the same number of sites as the high affinity GM-CSF receptor but a slightly higher Kd. Despite this competitive binding, IL-3 augmented AML blast proliferation in the presence of GM-CSF, indicating that the two growth factors have converging pathways in supporting blast proliferation. In striking contrast to AML blasts, GM-CSF binding to neutrophils was compatible with the presence of only one class of binding site of intermediate affinity (Kd approximately 100-160 pM). Furthermore, IL-3 does not compete for the binding of GM-CSF to neutrophils.
Leukemia 1990 May
PMID:IL-3 inhibits the binding of GM-CSF to AML blasts, but the two cytokines act synergistically in supporting blast proliferation. 220 26

125I-labeled recombinant human GM-CSF was used to identify and characterize receptors specific for this lymphokine on both a mature primary cell, human neutrophils, and on the undifferentiated promyelomonocytic leukemia cell line, HL-60. Human GM-CSF also bound to primary human monocytes and to the myelogenous leukemia cell line, KG-1, but not to any of the murine cells known to express the murine GM-CSF receptor. In addition, although some murine T lymphomas can express the GM-CSF receptor, none of the human cell lines of T cell lineage that we examined bound iodinated human GM-CSF. Binding to all cell types was specific and saturable. Equilibrium binding studies revealed that on all cell types examined, GM-CSF bound to a single class of high affinity receptor (100-500 receptors per cell) with a Ka of 10(9)-10(10)/M. More extensive characterization with neutrophils and HL-60 cells showed that in both cases, binding of GM-CSF was rapid at 37 degrees C with a slow subsequent dissociation rate that exhibited marked biphasic kinetics. Among a panel of lymphokines and growth hormones, only human GM-CSF could compete for binding of human 125I-GM-CSF to these cells. GM-CSF can not only stimulate the proliferation and differentiation of granulocyte/macrophage precursor cells, but can modulate the functional activity of mature granulocytes and macrophages as well. No significant differences in the kinetic parameters of receptor binding were seen between mature neutrophils and the undifferentiated promyelocytic leukemia cell line HL-60, indicating that maturation-specific responses to GM-CSF are not mediated by overt changes in the binding characteristics of the hormone for its receptor.
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PMID:Characterization of the cell surface receptor for human granulocyte/macrophage colony-stimulating factor. 301 35

Mutations of signal transducing molecules such as Ras have been shown to confer a growth advantage in leukaemic blasts and contribute to the pathogenesis of the disease. Alterations of signal transducing molecules other than Ras may play a role in leukaemogenesis. Knowledge of such mutations could also further our understanding of the normal signalling processes. We have therefore studied the coding sequence of the GM-CSF receptor alpha chain (GM-CSFR alpha) in patients with acute myeloid leukaemia (AML) and non-AML controls using single strand conformation polymorphism (SSCP) analysis. Abnormalities were detected in 4/32 AML patients (13%) and 2/15 non-AML controls (13%). Direct sequencing of PCR products revealed five different base substitutions. Three were conservative, two caused amino acid changes. The base substitution leading to amino acid change alanine to glycine at position 17 was found in both an AML patient and a control. It lies in the signal sequence and does not affect the mature protein. The other base change altering arginine to glutamine at position 164 is unlikely to influence the receptor structure as this structural position in the chain is not well conserved in members of the cytokine receptor family. Both amino acid changes were constitutive alterations as they could be demonstrated in the patients' children. The base changes described in the AML patients thus represent polymorphisms and do not contribute to the pathogenesis of AML.
Leukemia 1994 Sep
PMID:Analysis of mutations in the GM-CSF receptor alpha coding sequence in patients with acute myeloid leukaemia and haematologically normal individuals by RT-PCR-SSCP. 752 90

A fusion protein was synthesized consisting of the murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) gene spliced to a truncated form of the diphtheria toxin (DT390) gene coding for a molecule that retained full enzymatic activity, but excluded the native binding domain. The DT390-mGM-CSF hybrid gene was cloned into a vector under the control of an inducible promoter and the protein expressed in Escherichia coli. After induction, a protein was purified from inclusion bodies in accord with the deduced molecular weight of DT390 mGM-CSF. Cell-free studies of the adenosine diphosphate-ribosylating activity of DT390 mGM-CSF showed results that were similar to those of native DT. The DT390 mGM-CSF immunotoxin inhibited FDCP2.1d, a murine myelomonocytic tumor line expressing the GM-CSF receptor with an IC50 (concentration inhibiting 50% activity) of 5 x 10(-11) mol/L. The fusion toxin was specifically cytotoxic and directed by the GM-CSF portion of the molecule because addition of a monoclonal antibody directed against GM-CSF inhibited its ability to kill the cell line. Cell lines that do not express GM-CSF receptor were not inhibited by the fusion toxin. DT390 mGM-CSF was also able to specifically inhibit normal committed bone marrow (BM) progenitor cells as measured in clonal colony-forming unit granulocyte-macrophage assays. Together, these findings indicate that DT390 mGM-CSF may be useful as a novel tool for purging BM of contaminating leukemia cells or in vivo for eliminating residual leukemia cells. Also, it can be used to determine whether committed and/or noncommitted BM progenitor cells express the GM-CSF receptor.
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PMID:A murine cytokine fusion toxin specifically targeting the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor on normal committed bone marrow progenitor cells and GM-CSF-dependent tumor cells. 767 Jan 12

We have investigated the stimulative effects of mast cell growth factor (MGF) in primary acute myeloid leukemia (AML) in vitro. MGF stimulated DNA synthesis of purified leukemic blasts in eight out of 10 cases and colony formation in four cases in serum-free (SF) culture. MGF synergized with interleukin-3 (IL-3; four out of 10 cases), granulocyte-macrophage colony-stimulating factor (GM-CSF; three out of 10 cases), granulocyte colony-stimulating factor (G-CSF; six out of 10 cases), macrophage colony-stimulating factor (M-CSF; one out of 10 cases) and erythropoietin (EPO; one out of 10 cases) when added to culture in combination. Synergistic effects of MGF in combination with other CSFs were also seen in the colony assay. Antibodies against GM-CSF, M-CSF, G-CSF, and IL-6 did not inhibit the MGF response, suggesting that the stimulative effect of MGF was not mediated through autocrine release of those cytokines. Cell recovery data in liquid cultures that contained MGF, IL-3, or MGF + IL-3, indicated that both MGF and IL-3 augmented the maintenance of clonogenic cells as compared to nonsupplemented cultures, but the effect of the combination of IL-3 + MGF did not show synergy. In contrast, activation of DNA synthesis by MGF was abrogated in the presence of tumor necrosis factor (TNF; four out of 10 cases) and interleukin-4 (IL-4; two out of 10 cases). Fluorescence-activated cell sorting (FACS) analysis with anti c-kit antibodies revealed MGF receptor expression in eight out of nine cases, often in a subpopulation of the cells. Scatchard analysis of MGF receptors in two cases indicated the presence of 1460 and 41,500 (mean) binding sites, respectively, of high affinity (Kd 40-160 pmol/l). The MGF dose-response curve in the presence of IL-3 or GM-CSF resulted in a higher plateau of DNA synthesis, however no shift in the dose response was apparent. The respective reciprocal dose response relations to GM-CSF, IL-3, or G-CSF were similarly elevated when MGF was added. MGF did not alter IL-3 and GM-CSF receptor expression, nor did IL-3, GM-CSF, G-CSF, TNF, or IL-4 influence MGF binding to AML cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1993 Mar
PMID:Effects of mast cell growth factor on acute myeloid leukemia cells in vitro: effects of combinations with other cytokines. 768 Apr 1

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are hematopoietic growth factors which stimulate the proliferation and differentiation of myeloid progenitor cells. There is a considerable degree of overlap in target cell specificity and the functional effects of GM-CSF and IL-3. GM-CSF and IL-3 induce a nearly identical pattern of protein-tyrosine phosphorylation in certain cell lines, although their receptors have no kinase domains. Furthermore, their receptor complexes share one subunit (designated as beta). These observations raise the possibility that GM-CSF and IL-3 have a common signaling pathway. Here we show that both GM-CSF and IL-3 induce tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product (p92c-fes), a non-receptor protein-tyrosine kinase, in a human erythro-leukemia cell line, TF-1, which requires GM-CSF or IL-3 for growth. In addition, GM-CSF induces physical association between p92c-fes and the beta chain of the GM-CSF receptor. p92c-fes is therefore a possible signal transducer of several hematopoietic growth factors including GM-CSF and IL-3 through the common beta chain.
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PMID:c-fps/fes protein-tyrosine kinase is implicated in a signaling pathway triggered by granulocyte-macrophage colony-stimulating factor and interleukin-3. 768 76


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