Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to investigate the capability of cytokines to induce myeloid leukemia cells from G0 phase to the proliferative stage, blasts from 9 patients with AML and 1 patient with CML-MC were cultured with various cytokines (IL-3, GM-CSF, IL-3 + GM-CSF, G-CSF) for 48 hours or 96 hours in a serum-free culture system. Cells were analyzed by two-color flow cytometry, using PI and the monoclonal antibody Ki-67. The percentage of cells in G0 phase was reduced significantly when the cells were cultured with IL-3 (p < 0.01), GM-CSF (p < 0.01), and IL-3 + GM-CSF (p < 0.01) for 48 hours, as compared with the percentage of cells in G0 phase before culture. Moreover, the percentage of cells in S phase increased significantly when the cells were cultured with IL-3 (p < 0.01), GM-CSF (p < 0.02), and IL-3 + GM-CSF (p < 0.01) for 48 hours, as compared with the percentage of cells in S phase before culture. It is well known that many drugs which are widely used in the treatment of acute leukemia are cytotoxic mainly to proliferating cells, so that if quiescent G0 phase cells can be induced to the proliferative stage, the treatment of acute leukemia would become more effective. The present findings showed that a considerable variation was observed among individual patients in the induction of the G0 component to the proliferative stage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Capability of various cytokines to induce quiescent myeloid leukemia cells to the proliferative stage. 128 63

The response of neoplastic basophil/mast cell precursors to various hematopoietic factors was examined. Blastic or promyelocytic immature cells were obtained from six patients in basophilic crisis of chronic myelogenous leukemia. In all cases, after 14 days suspension culture more then 90% of the cells had basophilic features. 3H-thymidine uptake was markedly increased by the addition of GM-CSF in two cases, G-CSF in one, and IL-3 in two. In clonogenic cell assays, numerous colony formations were obtained when using the same growth factors as in the 3H-thymidine uptake assay. In addition, IL-3 induced colony formation in one case, despite a lack of thymidine uptake IL-4 had a synergistic effect on colony formation with IL-3 in one other case. None of the factors used showed any effect on differentiation. These findings indicate that the proliferation of neoplastic basophil/mast cell precursors may be regulated by various growth factors but response patterns are divergent.
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PMID:Neoplastic basophil/mast cell precursors from chronic myelogenous leukemia display heterogeneous responses for a hematopoietic factor. 137 56

A 36-year-old woman was referred to our hospital because of splenomegaly in February 1989. The leukocyte count was 55,500/microliter without hiatus leukemicus. The leukocyte alkaline phosphatase score was low (29). The bone marrow showed myeloid hyperplasia (24.8% myeloblasts) but no dysplastic change. The karyotype of the bone marrow cells was 46, XX and a diagnosis of Ph1 (-) CML was made. Treatment with VCR, 6MP and prednisolone made 7-month duration chronic phase, but the abnormal karyotype.[46, XX, i(17q)] gradually increased to 100% of bone marrow cells. The patient died in June 1990. The evidence that not only a BCR rearrangement but also messages of BCR/ABL fusion gene were negative made us able to differentiate this case from Ph1(-), BCR(+) CML. The addition of an i(17q) results in partial monosomy of 17q (17q13;p53 gene) and partial trisomy of 17q (17q11.2-12;G-CSF gene). We examined the rearrangement of p53 gene and G-CSF-dependent tumor cell growth in vitro, demonstrating one allelic loss of p53 gene and independent cell growth on G-CSF respectively. It is thought that in Ph1 (-), BCR (-) CML as well as in Ph1 (+) CML, an i(17q) is related to the progression but not to the initiation of these leukemias. However the precise mechanism, including p53 gene inactivation by point mutation, is still to be elucidated.
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PMID:[i(17q) appearing in acute phase in Ph1-negative, BCR-negative CML]. 163 23

Implantation of genetically manipulated fibroblasts is now coming considered to be one of the important methods for gene therapy. Before the clinical application of this method, we still need to resolve several problems encountered. We have recently developed a model system for the fibroblast-mediated cytokine supplementation gene therapy. BMGNeo (bovine papilloma virus-derived plasmid) (gifted from Dr. Karasuyama) was used for expression of hG-CSF cDNA or hIFN-alpha cDNA (gifted from Dr. Nagata). The two plasmid DNAs (BMGNeoG-CSF and BMGNeoIFN) were individually transfected into NIH/3T3 fibroblasts by the calcium phosphate coprecipitation method. Cell clones producing a large amount of G-CSF or IFN-alpha were selected by the enzyme immunoassay methods and were called G-CSF3T3 or IFN3T3 respectively. Nude mice implanted with G-CSF3T3 highly produced G-CSF in vivo. Remarkable increases in both blood neutrophils and spleen hematopoietic stem cells/progenitor cells (CFU-S, BFU-E, CFU-E, CFU-GM and CFU-MK) were observed. To regulate the production of G-CSF by G-CSF3T3 in vivo, we developed a diffusion chamber system as the cells can be treated easily. We could control the peripheral neutrophil count in nude mice. In the same manner, IFN3T3 was implanted in nude mice bearing a CML cell line, KU812. KU812 tumor growth was significantly suppressed by implantation of IFN3T3 into the chamber. The fibroblast-mediated cytokine supplementation gene therapy might be useful for the treatment of patients requiring for continuous dosing of cytokines.
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PMID:[Implantation of genetically manipulated fibroblasts into mice as a model of gene therapy--supplementations of human granulocyte colony-stimulating factor (hG-CSF) and interferon-alpha (IFN-alpha)]. 165 96

In this paper we demonstrate that maturing neoplastic cells from patients with chronic myelogenous leukemia (CML) constitutively produce G-CSF and are also receptive for this molecule. G-CSF functions as an autocrine growth factor in stable phase CML, and thus is responsible for divisions of maturing leukemic cells leading to an expansion of the compartment of mature cells. This observation is well in line with in vivo features of CML in stable phase, i.e., the hyperplasia of the mature granulocyte compartment. In acute blastic phase of CML expression of the G-CSF gene seems to be less common and not related to autonomous blast growth.
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PMID:Synthesis of granulocyte colony-stimulating factor and its requirement for terminal divisions in chronic myelogenous leukemia. 169 82

Juvenile chronic myelogenous leukemia (JCML) is a good model for the study of myeloproliferation because JCML hematopoietic progenitor cells grow in vitro at very low cell densities without the addition of exogenous stimulus. Previous studies have demonstrated that this proliferation is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF), and that removal of monocytes from the cell population before culture eliminates this "spontaneous" myeloproliferation, suggesting a paracrine role of monocyte stimulation. However, subsequent studies have shown that increased GM-CSF production from the JCML monocytes is not a consistent finding and therefore not a plausible sole mechanism. In examining hematopoietic growth factor dose-response curves, both JCML GM and erythroid nonadherent progenitor cell populations displayed a marked and selective hypersensitivity to GM-CSF. Responses to interleukin-3 and G-CSF were identical to control dose-response curves. This is the first demonstration of a myeloid leukemia in which hypersensitivity to a specific growth factor appears to be involved in the pathogenesis of the disease.
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PMID:Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. 170 4

More than 50% cure can be obtained with allogeneic bone marrow transplantation (BMT) when patients are transplanted in first remission of AML and ALL or chronic phase of CML. On the other hand, considerable progress has been made recently in treating acute leukemia with chemotherapy. Recent studies of intensive chemotherapy in adults with AML report approximately 40-50% 3-year disease-free survival (DFS). Accordingly, several prospective randomized clinical trials have been conducted on the use of BMT versus intensive chemotherapy in the treatment of AML. Significant differences in DFS were found only in a few studies though the results of BMT appear to be comparable or superior to chemotherapy. Therefore, the overall advantage of BMT in first remission AML is smaller than expected. We should know not whether to transplant or to perform chemotherapy, but rather whether to transplant in first remission or to perform chemotherapy first and reserve transplantation as salvage therapy. Recently acute promyelocytic leukemia has been successfully treated with differentiation therapy using all-trans retinoic acid. Low-dose aclarubicin has also been reported to be effective as differentiation therapy in some patients with myelodysplastic syndrome and atypical AML. With the advance of molecular biology of cytokines, several of them are now available for clinical use. G-CSF, GM-CSF and M-CSF are potent stimulators for the granulocyte-macrophage production; they are very effective for accelerating hematologic recovery after chemotherapy-induced myelosuppression or BMT. Interferon-alpha (IFN-alpha) has been used in the several studies. Furthermore, Ph chromosome positivity can be reduced with long-term administration of IFN-alpha; Ph-positive clone can be undetectable in some patients. Thus, IFN-alpha will be the choice of treatment for CML even if BMT is planned.
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PMID:[New trends in the treatment of leukemia]. 177 64

The binding of purified 125I-labeled murine granulocyte colony stimulating factor (125I-G-CSF) to normal and leukemic human cells was examined. Normal neutrophils and their precursors demonstrated specific labeling with 125I-G-CSF, whereas eosinophils, lymphocytes, and erythroid cells did not. Normal human promyelocytes demonstrated the highest binding among hemopoietic cells. Human myeloid leukemic cells also demonstrated consistent specific labeling with 125I-G-CSF. Normal promyelocytes and chronic myeloid leukemia promyelocytes demonstrated only transient clonal proliferation in vitro when stimulated by G-CSF, but this was not always the case with acute promyelocytic leukemic cells. The qualitative responsiveness of normal and leukemic cells to G-CSF was very similar despite heterogeneity in receptor numbers on individual cells. A subset of acute promyelocytic leukemic cells appeared unresponsive to stimulation by GM-CSF.
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PMID:Binding characteristics and proliferative action of purified granulocyte colony-stimulating factor (G-CSF) on normal and leukemic human promyelocytes. 244 1

The monocyte, monocyte conditioned media (MoCM), giant cell tumor conditioned media (GCT) and a purified colony-stimulating factor (G-CSF) promote granulocyte-macrophage progenitors (CFU-GM) growth and differentiation along the neutrophil lineage and also induce alkaline phosphatase (NAP) synthesis in the neutrophilic cells of normal subjects and of patients with chronic phase chronic myelogenous leukemia (CML). However, it is not known if granulocyte-macrophage-CSF (GM-CSF), macrophage-CSF (CSF-1) or other cytokines can induce NAP synthesis from the neutrophilic cells of CML patients. The objective of this study were (a) to ascertain which of the three CFU-GM CSFs would induce NAP synthesis, and (b) to test if any of the other cytokines--interleukin-1 (IL-1), interleukin-2 (IL-2), alpha- and gamma-interferons (alpha-INF and r-INF), and phytohemagglutinin-stimulated T-cell conditioned media (TCM) would induce NAP synthesis. Light density cells obtained from the blood of patients with chronic phase CML were depleted of T cells and monocytes. These cells were cultured with various amounts of G-CSF, GM-CSF, CSF-1, IL-1, IL-2, alpha-INF, r-INF, MoCM, GCT and TCM in a suspension culture system over 6-7 days. Evaluation of the cultures indicated that G-CSF, MoCM and GCT, but not the other factors or cytokines, consistently induced NAP synthesis in a dose-dependent manner. Actinomycin-D and puromycin in separate cultures inhibited NAP synthesis without any significant reduction in cell counts. This indicated that NAP is not prepackaged in neutrophilic cells, and its synthesis occurs by a sequential transcription at the DNA level and translation at the ribosomal level. Our results suggest that the molecule which is responsible for promotion of CFU-GM growth and differentiation along the neutrophilic cell lineage is also responsible for derepression of NAP gene and initiation of NAP synthesis.
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PMID:Granulocyte colony-stimulating factor (G-CSF) induces synthesis of alkaline phosphatase in neutrophilic granulocytes of chronic myelogenous leukemia patients. 245 37

The effects of transforming growth factor beta 1 or beta 2 (TGF-beta 1 or -beta 2) on the in vitro proliferation and differentiation of normal and malignant human hematopoietic cells were studied. Both forms of TGF-beta suppressed both the normal cellular proliferation and colony formation induced by recombinant human interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the presence of GM-CSF or IL-3, optimal concentrations of TGF-beta (400 pmol/L) inhibited colony formation by erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor cells by 90% to 100%, whereas granulocyte or monocyte cluster formation was not inhibited. In contrast, neither form of TGF-beta had any effect on G-CSF-induced hematopoiesis. The suppressive action appeared to be mediated directly by TGF-beta since antiproliferative responses were also observed in accessory cell-depleted bone marrow cells. In contrast to normal bone marrow cells, both GM- and G-CSF-induced proliferation of cells from patients with chronic myelogenous leukemia were suppressed in a dose-dependent manner by TGF-beta. Differential effects of TGF-beta on the proliferation of established leukemic lines were also observed since most cell lines of myelomonocytic nature studied were strongly inhibited where erythroid cell lines were either insensitive or poorly inhibited by TGF-beta. These results suggest that TGF-beta is an important modulator of human hematopoiesis that selectively regulates the growth of less mature hematopoietic cell populations with a high proliferative capacity as opposed to more differentiated cells, which are not affected by TGF-beta.
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PMID:Transforming growth factor beta selectively inhibits normal and leukemic human bone marrow cell growth in vitro. 246 Jan 53


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