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

Mast cell growth factor (MGF), the ligand for the c-kit receptor, has been shown to be a hematopoietic growth factor that preferentially stimulates the proliferation of immature hematopoietic progenitor cells (HPC). We studied the effect of MGF on the in vitro growth of clonogenic leukemic precursor cells in the presence or absence of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or erythropoietin (EPO). Leukemic blood and bone marrow cells from patients with various types of acute myeloid leukemia (AML), chronic myeloid leukemia (CML) in chronic phase, as well as bone marrow samples from patients with myelodysplastic syndromes (MDS) were studied. MGF as a single factor did not induce significant colony formation by clonogenic leukemic precursor cells. In the presence of IL-3 and/or GM-CSF, MGF weakly stimulated the colony formation by clonogenic precursor cells from patients with AML. In contrast, in the presence of IL-3 and/or GM-CSF, MGF strongly induced both size and number of leukemic colonies from patients with CML in chronic phase. Furthermore, in the presence of EPO, MGF strongly stimulated erythroid colony formation by CML precursor cells. Cytogenetic analysis of the colonies showed that all metaphases after 1 week of culture were derived from the leukemic clone. In patients with MDS, MGF strongly stimulated myeloid colony formation in the presence of IL-3 and/or GM-CSF (up to fourfold), and erythroid colony formation in the presence of EPO (up to eightfold). Not only the number, but also the size of the colonies increased. In the presence of MGF, the percentage of normal metaphases increased in three patients tested after 1 week of culture compared with the initial suspension, suggesting that the normal HPC were preferentially stimulated compared with the preleukemic precursor cells. In the absence of exogenous EPO and in the presence of 10% human AB serum, MGF in the presence of IL-3 and/or GM-CSF induced erythroid colony formation from normal bone marrow and patients with MDS or CML, illustrating that MGF greatly diminished the EPO requirement for erythroid differentiation. These results indicate that MGF may be a candidate as a hematopoietic growth factor to stimulate normal hematopoiesis in patients with acute myeloid leukemia, or with myelodysplastic syndromes.
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PMID:Effect of mast cell growth factor (c-kit ligand) on clonogenic leukemic precursor cells. 163 26

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

We have analyzed the ability of highly purified preparations of human NK cells to produce CSF. NK cells, purified by negative selection from 10-d cultures of PBMC incubated with irradiated B-lymphoblastoid cell lines, were stimulated with rIL-2, FcR(CD16) ligands (particulate immune complexes or anti-CD16 antibodies bound to Sepharose), a combination of CD16 ligands and rIL-2, or the phorbol diester phorbol dibutyrate (PDBu) together with the Ca2+ ionophore A23187. Both rIL-2 and CD16 ligands induce accumulation of GM-CSF mRNA in NK cells and the combined effect of the two stimuli is synergistic. Maximal accumulation of GM-CSF mRNA is observed after PDBu/A23187 stimulation. The participation of contaminant T cells in the observed expression of the GM-CSF gene is excluded because CD16 ligands do not stimulate T cells and CD3 ligands, powerful stimulators of T cells, are inactive on NK cells. Accumulation of CSF-1 mRNA is observed only in NK cells stimulated with both CD16 ligands and rIL-2, whereas accumulation of IL-3 mRNA is observed only in NK cells stimulated with PDBu/A23187. Transcripts of the G-CSF, IL-1 alpha, and IL-1 beta genes were never detected in NK cells in these experiments. The kinetics of accumulation of GM-CSF and CSF-1 mRNA in NK cells stimulated with CD16 ligands and rIL-2 peaked at 2-4 h and was slower than that of TNF and IFN-gamma mRNA, which peak at 1 h. GM-CSF was precipitated from the supernatant fluids of NK cells stimulated with PDBu/A23187 and its biological activity was demonstrated by the ability of the supernatants to sustain proliferation of the TALL-101 cell line or CML blasts. Biological activity of IL-3 and CSF-1 was demonstrable in supernatant fluids of NK cells stimulated with PDBu/A23187 and CD16 ligands/rIL-2, respectively.
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PMID:Production of hematopoietic colony-stimulating factors by human natural killer cells. 252 57

Activated T cells secrete a glycoprotein (P-cell-stimulating factor; PSF) that stimulates the proliferation of many types of haemopoietic progenitor cells and the pluripotential haemopoietic stem cells. Based on experiments in mice, it is proposed that some proliferative disorders of the pluripotential haemopoietic stem cell or its progeny may result from the abnormal production and secretion of PSF by these cells themselves. The secreted PSF binding to specific receptors on the surface of these cells causes autostimulation and uncontrolled proliferation. Acute non-lymphocytic leukaemias and the late stages of Hodgkin's disease might be due to such autostimulation. More chronic proliferative diseases (eg, chronic myeloid leukaemia and the early stages of Hodgkin's disease) may involve the expansion of an abnormal, immortalised, clone of pluripotential haemopoietic stem cells or committed haemopoietic progenitor cells that are not autonomous but remain strictly dependent for their proliferation and survival on the presence of exogenous PSF.
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PMID:Role of a single haemopoietic growth factor in multiple proliferative disorders of haemopoietic and related cells. 614 37

Cytokines are a class of signal peptides which represent a major communication network in living organism. Over the last decade, the discovery, cloning and purification of hematopoietic cytokines (interleukins, hematopoietic growth factors) has increased our understanding of the regulation, proliferation, differentiation and function of hematopoietic cells. More recently, the large scale production of the recombinant forms of these molecules has enabled to treat the patients with pharmacologic doses of cytokines. The therapeutic activity of interferon-alpha (IFN-alpha) has been demonstrated in patients with chronic myeloid leukaemia and other chronic myeloproliferative syndromes. IFN-gamma is useful in the prevention of infections in patients with chronic granulomatous disease. Erythropoietin (EPO) was the first hematopoietic growth factor available for clinical use, initially to treat anaemia in renal failure patients. The next cytokines introduced into the clinic were granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF). They are used successfully in haematological malignant disorders to stimulate granulopoiesis after chemotherapy or bone marrow transplantation and to help mobilise marrow stem cells for peripheral blood stem cell transplantation. Interleukin (IL)-1, -2, -3, -4, -6 and -11 have been tested in clinical trials. However, the value of these agents remains to be established.
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PMID:[Cytokines in the treatment of blood diseases]. 754 26

Since the first successful attempt in 1985, peripheral blood stem cell transplants are increasingly performed worldwide and should now be considered as an essential therapeutic weapon against onco-hematological diseases. Their development has benefited greatly from a rapid concomitant advance of experimental knowledge regarding the nature of hematopoietic progenitor cells. For this reason and also for technical ones, until now these transplants generally have been autotransplants. Although one of the main reasons to use blood rather than bone marrow-derived stem cells was that they might carry less risk of relapse than autologous bone marrow cells, the lack of clinical randomized trials and/or the short follow-up make conclusions difficult so far in terms of disease-free and overall survival. Probably the risk of relapse also depends on the type of disease, on prior chemotherapies, on the type of peripheral stem cell mobilization regimen and on the number of blood-derived cells transplanted. Nevertheless, there are several major clinical indications for autologous blood stem cell transplant: acute nonlymphoblastic leukemias (ANLL), low-grade non-Hodgkin's lymphomas, multiple myeloma, some solid tumors, and even chronic myeloid leukemia. Now well-demonstrated advantages add a socioeconomic interest to this technique. The speed of post-transplant hematopoietic recovery induces a briefer hospitalization and a lower cost of the procedure, which represents "per se" important progress. Furthermore, the increasing use of hematopoietic growth factor(s) at time of blood-derived cell mobilization should increase the safety of the procedure. Also new trends are currently being developed: autotransplants with purified peripheral CD34+ cells; addition of adjuvant immunotherapy to induce graft-versus-tumor effect, which is lacking in autotransplant; and transplants using allogenic umbilical cord blood progenitors. Allogenic blood cell transplants might also be developed, provided that blood cells would be less likely to cause graft-versus-host disease (GVHD) than bone marrow, which is still not verified. Finally, the use of blood-derived cells as a vehicle for gene therapy should develop greatly in the near future.
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PMID:Peripheral blood stem cell transplantations: past, present and future. 810 Apr 62

The FLT3 gene encodes a protein that appears to function as a receptor for a hematopoietic growth factor; together with the KIT and FMS receptors, FLT3 belongs to the superfamily of receptors with tyrosine kinase activity. We examined the expression of FLT3 mRNA in 36 human leukemia-lymphoma cell lines using Northern blot analysis. FLT3 transcripts were found in seven of seven pre B-ALL cell lines (derived from cases with pre B-acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast crisis), and in one of six B-cell lines (namely in a cell line established from a hairy cell leukemia). FLT3 message was not detected in five T-cell, five myeloid, four monocytic, four erythroid and five megakaryocytic cell lines. Two major mRNA species were expressed differentially by positive cell lines. KIT mRNA expression was also investigated in the same panel of cell lines, but was found only in cell lines with erythroid and megakaryocytic features (and not in any of the FLT3-positive cell lines). The pattern of expression of FLT3 contrasts with the transcription of FMS and KIT and suggests that the FLT3 product may play a role primary in immature lymphoid cells.
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PMID:Expression of the FLT3 gene in human leukemia-lymphoma cell lines. 818 45

There is now strong evidence that the BCR-ABL gene product (P210) of the Philadelphia chromosome plays a crucial role in the pathogenesis of chronic myeloid leukaemia (CML). That is why antisense strategies aiming at inhibiting P210 expression for research or therapeutic purposes are increasingly investigated. Two main tools are currently available in this respect: oligonucleotides and retrovirally transduced antisense sequences. In this paper, we discuss the potential advantages and drawbacks of each approaches and report experimental evidences showing the feasibility of the second one in a murine lymphoid cell line (BaF3) expressing P210 upon retroviral transduction of the complete BCR-ABL cDNA. A retroviral vector was used to introduce selected antisense and sense sequences into this cell line, that P210 expression had rendered Interleukin-3 (IL3) independent. The antisense transcripts generated under the control of MoMLV promoter specifically killed BaF3 cells in the absence of IL3 and stably inhibited P210 expression. Retrovirally transduced antisense sequences can thus successfully achieve stable suppression of P210 and may be used to study further the mechanisms by which P210 is transforming cells. The effect on CML cell lines and fresh CML cells, in bone marrow cultures, remains to be investigated before considering this technique for in vitro selective suppression of Philadelphia-positive haematopoiesis.
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PMID:Inhibition of P210 expression in chronic myeloid leukaemia: oligonucleotides and/or transduced antisense sequences. 825 87

We report a case of chronic myelogenous leukemia (CML) with pruritic erythroderma. Hyperhistaminemia, elevated level of plasma interleukin-3 (IL-3), and moderate basophilia were noted in this case. His skin manifestation was resistant to topical corticosteroid therapy and exacerbated in parallel with leukocyte count, plasma histamine and IL-3 levels. To identify localization and production of IL-3 in our case, we performed in situ hybridization on peripheral blood cells and skin biopsy specimen, and detected IL-3 mRNA in myelogenic cells in both specimens.
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PMID:Leukemic erythroderma with elevated plasma IL-3 and hyperhistaminemia: in situ expression of IL-3 mRNA in leukemic cells. 859 65

The novel hematopoietic growth factor FLT3 ligand (FL) is the cognate ligand for the FLT3, tyrosine kinase receptor (R), also referred to as FLK-2 and STK-1. The FLT3R belongs to a family of receptor tyrosine kinases involved in hematopoiesis that also includes KIT, the receptor for SCF (stem cell factor), and FMS. the receptor for M-CSF (macrophage colony- stimulating factor). Restricted FLT3R expression was seen on human and murine hematopoietic progenitor cells. In functional assays recombinant FL stimulated the proliferation and colony formation of human hematopoietic progenitor cells, i.e. CD34+ cord and peripheral blood, bone marrow and fetal liver cells. Synergy was reported for co-stimulation with G-CSF (granulocyte-CSF). GM-CSF (granulocyte-macrophage CSF), M-CSF, interleukin-3 (IL-3), PIXY-321 (an IL-3/GM-CSF fusion protein) and SCF. In the mouse, FL potently enhanced growth of various types of progenitor/precursor cells in synergy with G-CSF, GM-CSF, M-CSF, IL-3, IL-6, IL-7, IL-11, IL-12 and SCF. The well-documented involvement of this ligand-receptor pair in physiological hematopoiesis brought forth the question whether FLT3R and FL might also have a role in the pathobiology of leukemia. At the mRNA level FLT3R was expressed by most (80-100%) cases of AML (acute myeloid leukemia) throughout the different morphological subtypes (MO-M7), of ALL(acute lymphoblastic leukemia) of the immunological subtypes T-ALL and BCP-ALL (B cell precursor ALL including pre-pre B-ALL, cALL and pre B-ALL), of AMLL (acute mixed-lineage leukemia), and of CML (chronic myeloid leukemia) in lymphoid or mixed blast crisis. Analysis of cell surface expression of FLT3R by flow cytometry confirmed these observations for AML (66% positivity when the data from all studies are combined), BCP-ALL (64%) and CML lymphoid blast crisis (86%) whereas less than 30% of T-ALL were FLT3R+. The myeloid, monocytic and pre B cell type categories also contained the highest proportions of FLT3R+ leukemia cell lines . In contrast to the selective expression of the receptor, FL expression was detected in 90-100% of the various cell types of leukemia cell lines from all hematopoietic cell lineages. The potential of FL to induce proliferation of leukemia cells in vitro was also examined in primary and continuously cultured leukemia cells. The data on FL-stimulated leukemia cell growth underline the extensive heterogeneity of primary AML and ALL samples in terms of cytokine-inducible DNA synthesis that has been seen with other effective cytokines. While the majority of T-ALL (0-33% of the cases responded proliferatively; mean 11%) and BCP-ALL (0-30%; mean 20%) failed to proliferate in the presence of FL despite strong expression of surface FLT3R, FL caused a proliferative response in a significantly higher percentage of AML cases (22-90%; mean 53%). In the panel of leukemia cell lines examined only myeloid and monocytic growth factor- dependent cell lines increased their proliferation upon incubation with FL, whereas all growth factor-independent cell lines were refractory to stimulation. Combinations of FL with G-CSF, GM-CSF, M-CSF, IL-3, PIXY- 321 or SCF and FL with IL-3 or IL-7 had synergistic or additive mitogenic effects on primary AML and ALL cells, respectively. The potent stimulation of the myelomonocytic cell lines was further augmented by addition of bFGF (basic fibroblast growth factor), GM-CSF, IL-3 or SCF. The inhibitory effects of TGF-beta 1 (transforming growth factor-beta 1) on FL- supported proliferation were abrogated by bFGF. Taken together, these results demonstrate the expression of functional FLT3R capable of mediating FL- dependent mitogenic signaling in a subset of AML and ALL cases further underline the heterogeneity of AML and ALL samples in their proliferative response to cytokine.
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PMID:Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. 861 33


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