Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene was studied by Northern blot analysis in normal human hematopoietic cells and a series of leukemias. GM-CSF messenger (m)RNA was detected in activated T cells, but not in normal bone marrow cells, monocytes, or nonactivated T cells. In contrast, leukemic cells from 11 of 22 cases of acute myeloblastic leukemia expressed GM-CSF transcripts. Biologically active CSF was detected in supernatant conditioned by 6 of these 11 leukemias. Expression of the GM-CSF gene was not detected in "common" (pre-B cell) acute lymphoblastic leukemia (11 cases tested) or chronic myeloid leukemia (4 cases tested). These results show that the GM-CSF gene is constitutively expressed in a subset of patients with AML, and further suggest that expression of this gene could contribute to the abnormal growth properties characteristic of AML.
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PMID:Constitutive expression of the granulocyte-macrophage colony-stimulating factor gene in acute myeloblastic leukemia. 349 36

In order to assess the response of acute myeloid leukemia colony-forming cells (AML-CFU) to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), AML blasts of 20 patients were cultured in a colony assay supplemented with titrated concentrations of rGM-CSF. In 16 cases rGM-CSF was able to induce AML colonies. In eight cases maximal clonogenic cell proliferation was obtained with 100 U rGM-CSF/ml alone (type I response). In eight other cases, however, maximal colony numbers were reached only after the addition of low concentrations of PHA-leukocyte conditioned media (PHA-LCM) to the rGM-CSF containing cultures (type II response). These values could not be obtained with higher doses of rGM-CSF (500 U/ml) or PHA-LCM separately. Thus in this subgroup, optimal AML colony formation depended on rGM-CSF plus an additional factor. Finally, in 4 of 20 cases rGM-CSF alone (100 U, 1000 U/ml) was not capable of inducing any AML colonies in vitro (type III). In these latter cases proliferation of AML-CFU could be achieved only by supplementing PHA-LCM. We conclude that GM-CSF is a stimulator of the in vitro proliferation of AML clonogenic cells. However, in a majority of these cases, i.e., 12 out of 20, AML-CFU require an additional factor for optimal proliferation which is produced by PHA-stimulated leukocytes.
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PMID:Patterns of acute myeloid leukemia colony growth in response to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). 349 34

A clonal growth of leukemic cells from the bone marrow of a patient with acute myeloid leukemia was observed in vitro for more than 20 months. Cytochemical and electron microscopic studies of the cells growing in vitro demonstrated that they were blast cells, differentiated granulocytes, and macrophages. They showed complete dependence on granulocyte-macrophage colony-stimulating factor for colony formation in agar. In addition to the presence of granulocytic colonies, some showed granulocyte-macrophage characteristics, suggesting that bipotential cells were also involved in long-term growth. Initially, they showed localized proliferation on or around giant fibroblast-like cells. Even after constant growth was established, attempts to transfer these cells were unsuccessful, and their growth was confined to the original flasks. These observations seen to indicate that their growth was not autonomous but dependent on the adherent cells in the flasks. This was also supported by a coculture experiment in which the cells were demonstrated to proliferate for 4 months only in the presence of normal bone marrow particles and bone marrow particle-derived feeder layers. These results suggest that, in some cases, long-term growth of leukemic cells can be induced in vitro by the cocultivation of bone marrow stromal cells.
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PMID:Long-term and dependent growth of human leukemic blast cells with granulocyte-macrophage differentiation in vitro. 657 54

The effect of interleukin 10 (IL-10) on proliferation and cytokine secretion by acute myelogenous leukemia (AML) blast cells was investigated in vitro. IL-10 inhibited spontaneous AML blast proliferation for a majority of patients, whereas in the presence of exogenous growth factors (granulocyte-stimulating factor, G-CSF; granulocyte-macrophage colony-stimulating factor, GM-CSF; interleukin 3) the IL-10 effect on blast proliferation showed a wide variation depending on the individual AML patient. IL-10 seemed to cause an irreversible inhibitory effect on AML blasts, as inhibition could also be demonstrated when IL-10 was present only during the initial preincubation of the leukemia cells. IL-10 also inhibited AML blast colony formation. However, independent of the effect on AML blast proliferation, IL-10 decrease cytokine secretion from AML blast cells for all patients, as demonstrated for IL-1 alpha, IL-1 beta, tumor necrosis factor-alpha, GM-CSF and interleukin 6. IL-10 did not inhibit development of apoptosis in AML blasts cultured in vitro. Expression of complement receptors and capability to adhere and internalize bacteria by AML blasts were not altered by IL-10.
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PMID:Effects of interleukin 10 on blast cells derived from patients with acute myelogenous leukemia. 747 83

A novel hematopoietic growth factor for primitive hematopoietic progenitor cells, the ligand for the flt3/flk2 receptor, (FL), has been recently purified and its gene has been cloned. In the present study, we investigated the effects of FL on the proliferation and differentiation of normal and leukemic myeloid progenitor cells. We demonstrate that FL is a potent stimulator of the in vitro growth of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), or G-CSF-dependent granulocyte-macrophage committed precursors from Lin- CD34+ bone marrow cells of normal donors. By contrast, FL does not affect the growth of erythroid-committed progenitors even in the presence of erythropoietin. The effect of FL on the proliferation and on the in vitro growth of clonogenic leukemic precursor cells was studied in 54 acute myeloid leukemia (AML) cases. Fresh leukemia blasts from 36 of 45 patients with AML significantly responded to FL without any relation to the French-American-British (FAB) subtype. FL stimulated the proliferation of leukemic blasts in a dose-dependent fashion. Synergistic activities were seen when FL was combined with G-CSF, GM-CSF, IL-3, or stem cell factor (SCF). FL as a single factor induced or increased significantly colony formation by clonogenic precursor cells from 21 of 24 patients with AML. In the presence of suboptimal and optimal concentrations of G-CSF, GM-CSF, IL3, SCF, or a combination of all factors, FL strongly enhanced the number of leukemic colonies (up to 18-fold). We also evaluated the induction of tyrosine phosphorylated protein on FL stimulation in fresh AML cells. We demonstrate that, on FL stimulation, a band of phosphorylated protein(s) of about 90 kD can be detected in FL-responsive, but not in FL-unresponsive cases. This study suggests that FL may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor with other cytokines.
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PMID:Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors. 749 67

Granulocyte colony-stimulating factor (G-CSF) is a potent stimulator of the growth of normal and malignant hematopoietic cells and synergizes with other factors such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The action of G-CSF is mediated through a specific membrane receptor, however it is not clear if all of the effects of G-CSF are direct or indirect. As a step towards addressing this problem, a recombinant diphtheria toxin (DT)-related human G-CSF fusion protein has been constructed and purified from E. coli. The 70,000 dalton chimeric protein has immunologic determinants characteristic of both DT and G-CSF. At high concentrations, DAB486-G-CSF is cytotoxic towards G-CSF-dependent OCI/AML1 cells, but not factor independent OCI/AML3 cells; colony formation by G-CSF-responsive leukemic blasts from a patient with acute myeloblastic leukemia (AML) was also inhibited. The G-CSF fusion toxin displayed ADP-ribosyltransferase activity in a cell-free system. Genetic conjugation of G-CSF to an enzymatically inactive DT mutant, CRM197, resulted in a 200-fold reduction in the ability of G-CSF to stimulate normal bone marrow colony formation. These results suggest that fusion of G-CSF to DT sequences interferes with some of the activity but not the specificity of the ligand binding domain of the molecule. Nevertheless, DAB486-G-CSF may be included with the increasing number of other toxin-hormone fusion proteins whose toxicity is directed towards specific receptor-bearing cells, and may represent a novel approach towards the study and treatment of leukemia.
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PMID:Cytotoxicity of a recombinant diphtheria toxin-granulocyte colony-stimulating factor fusion protein on human leukemic blast cells. 750 48

The relative affinity of recombinant human interleukin-3 (IL-3) binding to normal rhesus monkey bone marrow cells was found to be 25- to 50-fold less than that of homologous IL-3, which explained the species specificity of human IL-3 observed when tested in Macaca species. In contrast, only a small difference was found between human and rhesus monkey IL-3 in relative binding affinity for receptors on human acute myelogenous leukemia (AML) cells, which confirmed that the species specificity of IL-3 is largely unidirectional. The biological significance of the findings was demonstrated by direct in vivo comparison of the effects of high-dose recombinant rhesus monkey and human IL-3. The binding characteristics of IL-3 receptors on rhesus monkey bone marrow and peripheral blood cells were further characterized by specific binding of radiolabeled rhesus monkey IL-3. Scatchard analysis of two bone marrow samples demonstrated high-affinity IL-3 receptors (25 and 80 sites/cell, respectively; equilibrium dissociation constants [Kd] of 8 and 3 pM/L) as well as low-affinity receptors (1070 and 1290 sites/cell; equilibrium dissociation constants of 2600 and 1200 pM/L). In addition, IL-3 receptor expression was also detected on purified CD34-positive bone marrow cells. Competition by human granulocyte-macrophage colony-stimulating factor (GM-CSF) of IL-3 binding to high- or low-affinity receptors on rhesus monkey peripheral blood and bone marrow cells could not be demonstrated, which may indicate that the growth factor-specific alpha-subunits of the GM-CSF and IL-3 receptors are expressed predominantly on different cell types.
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PMID:Interleukin-3 (IL-3) receptors on rhesus monkey bone marrow cells: species specificity of human IL-3, binding characteristics, and lack of competition with GM-CSF. 750 88

Laboratory studies have suggested that hematopoietic growth factors (GF), combined with cytosine-arabinoside (Ara-C) can enhance cytotoxic effects of this agent against acute myeloid leukemia (AML) cells. While clinical trials based on this growth factor/chemotherapy combination (GF/CT) are progressing with discordant results, further information regarding the underlying mechanisms have been reported supporting this rationale and requiring additional investigation. To assess the role of cytokinetic changes in the GF/CT strategy and to evaluate if chemotherapeutic agents regimens other than Ara-C, when combined with GF, can enhance their cytotoxic effects, we have primed AML blasts with two cytokine combinations and then exposed these cells to the S-phase specific agent Ara-C as well as to the phase non-specific drug daunorubicin (DNR) and to the alkylating agent 4-hydroperoxycyclophosphamide (4-HC). The two cytokine combinations used for priming AML blasts were: (i) interleukin-3 (IL-3) + granulocyte-macrophage colony-stimulating factor (GM-CSF) + granulocyte colony-stimulating factor (G-CSF); and (ii) GM + G-CSF. Cytokinetic analysis in ten AML samples and clonogenic growth of leukemic colonies (CFU-L) in methylcellulose were used to detect proliferative and cytotoxic effects on AML samples. We report that in AML clonogenic cell growth can be stimulated by cytokines in 50% of the samples (4/8), and that Ara-C sensitization clearly occurs in two out of these four samples. Among the different cytokine combinations tested, the one containing IL-3 was the most effective through a cytokinetic mechanism consistent with recruitment (averaged G0 decrease p = 0.04; S-phase increase p = 0.005). Furthermore we observed increased cytotoxicity also to the phase non-specific drugs DNR and 4-HC, which may be mediated by other mechanisms recently described. We conclude that GF/CT combinations may also be beneficial in regimens containing drugs other than Ara-C, used for AML treatment, including bone marrow transplantation conditioning regimens.
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PMID:Combination of hematopoietic growth factors containing IL-3 induce acute myeloid leukemia cell sensitization to cycle specific and cycle non-specific drugs. 751 44

Blast cells from 70% of patients with acute myeloid leukemia (AML) show some evidence of in vitro autonomous growth, which appears to be related to the autocrine secretion of growth factors, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF). In the majority of cases, the growth factors appear to be involved in classical extracellular autocrine or paracrine loops with neutralizing antibodies to the relevant cytokine inhibiting growth. In a minority, however, antibodies do not inhibit growth despite evidence of secretion of the cytokine. There is evidence for intracellular autocrine loops in murine leukemic cell lines. In this study, we wished to investigate for the presence of such intracellular loops involving GM-CSF in AML blast cells. Blast cells from 11 patients with AML were cultured in the presence of either neutralizing GM-CSF antibody or an antisense oligonucleotide directed against GM-CSF. We also studied the effect of the oligonucleotide on the autonomous growth of cells whose production of GM-CSF had been apparently abolished by either interleukin-1 receptor antagonist (IL-1Ra) or following blast cell purification using the CD34 antigen. The autonomous growth of the blast cells from nine of the 11 patients was inhibited by the antisense oligonucleotide (but not by the control sense oligonucleotide). However, only six of the nine were inhibited by the anti-GM-CSF antibody. Similarly, in one patient whose CD34 purified blast cells continued to show a high degree of autonomous growth but did not produce detectable GM-CSF, growth was inhibited by the antisense oligonucleotide but not by antibody, while in another patient whose cells were inhibited by IL-1Ra with, again, loss of detectable GM-CSF, growth could be further inhibited by the addition of the oligonucleotide but not the antibody. These studies provide evidence that intracellular autocrine loops involving GM-CSF are involved in the autonomous growth of some AML blast cells.
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PMID:Evidence for internal autocrine regulation of growth in acute myeloblastic leukemia cells. 751 89

In vivo, growth factors are currently investigated for their capacity to trigger leukemic stem cells into cycle and thus overcome kinetic drug resistance. In this study, the susceptibility of leukemic clonogenic cells to individual growth factors was related to cytosine-arabinoside (Ara-C) sensitivity. The effects of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (G-CSF), granulocyte colony-stimulating factor (G-CSF), and combinations of these recombinant hematopoietic factors were tested on blast cells of nine acute myeloid leukemia (AML) patients. Growth factor responses were assessed in semi-solid clonogenic assay and in a 10-day liquid culture followed by clonogenic assay. Heterogeneity in growth factor response was observed in both test systems, resulting in a variable pattern for individual leukemias. In the majority of cases (six of nine) the response patterns in the semi-solid and liquid cultures were divergent. To test the Ara-C sensitivity, leukemic blasts were exposed in liquid to various concentrations of Ara-C in the absence and presence of preselected growth factors. After 10 days, the number of surviving leukemic colony-forming cells (CFU-L) was assessed. Exposure to Ara-C in the presence of optimal stimulatory factor(s) resulted in a 3- to 1000-fold increase of the Ara-C toxicity in seven patients. The Ara-C concentrations resulting in 50% inhibition of clonogenicity (ID50) were 0.48-123 x 10(-8) M Ara-C in the absence of stimulatory growth factors, versus only 0.12-0.40 x 10(-8) M Ara-C in the presence of these factors. In two patients, addition of one or more factors neither increased the number of CFU-L in liquid nor enhanced the Ara-C toxicity. Even in the absence of growth factors the ID50 values in these cases were as low as 0.20 and 0.28 x 10(-8) M Ara-C and in the same range as the ID50 values observed with maximum growth factor stimulation in the other seven patients. These results indicate that Ara-C cytotoxicity can be enhanced by individually selected, clonogenic cell growth-promoting hematopoietic factors.
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PMID:In vitro response of blasts to IL-3, GM-CSF, and G-CSF is different for individual AML patients: factors that stimulate leukemic clonogenic cells also enhance Ara-C cytotoxicity. 751 90


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