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

Alterations in genes that function in normal growth and development have been linked to malignant cell transformation. The mononuclear phagocyte colony-stimulating factor (CSF-1 or M-CSF) is a polypeptide growth factor synthesized by mesenchymal cells, which stimulates the survival, proliferation, and differentiation of haematopoietic cells of the monocyte-macrophage series. Multiple forms of soluble CSF-1 are produced by proteolytic cleavage of membrane-bound precursors, some of which are stably expressed at the cell surface. The c-fms proto-oncogene encodes the CSF-1 receptor, which is composed of an extracellular ligand-binding domain linked by a single membrane-spanning segment to a cytoplasmic tyrosine-specific protein kinase domain. Whereas the tyrosine kinase activity of the normal receptor is stimulated by CSF-1, mutations in the c-fms gene can constitutively activate the kinase to provide growth-stimulatory signals in the absence of the ligand. Oncogenic activation of the c-fms gene product appears to involve removal of a negative regulatory tyrosine residue near the carboxyl terminus of the receptor and one or more additional mutations that may simulate a conformational change induced by CSF-1 binding. Expression of the human c-fms gene in mouse NIH-3T3 cells confers a CSF-1 stimulated growth phenotype, indicating that receptor transduction is sufficient for fibroblasts to respond to a haematopoietic growth factor. In contrast, the v-fms oncogene induces factor-independent growth and tumorigenicity in factor-dependent myeloid cell lines, and contributes to the development of proliferative disorders of multiple haematopoietic lineages when introduced into murine bone marrow progenitors. Aberrant expression of an endogenous c-fms gene secondary to proviral insertion and transcriptional activation has also been implicated in virus-induced myeloblastic leukaemia in mice. The c-fms and CSF-1 genes have been mapped on the long arm of human chromosome 5, a region that frequently undergoes interstitial deletions in certain haematopoietic disorders including acute myelogenous leukaemia. The study of CSF-1 and its receptor should provide information concerning the role of tyrosine kinases in regulating the normal growth and differentiation of haematopoietic cells and in contributing to their malignant transformation.
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PMID:The colony-stimulating factor 1 (CSF-1) receptor (c-fms proto-oncogene product) and its ligand. 297 16

The human monoblast leukemia line U937 is growth inhibited and induced to express various characteristics of mature monocytes by lymphokines (LK) and other cytokines. Previous experiments have shown that interferon-gamma (IFN-gamma) is responsible for some but not all of the differentiation-inducing effects on U937. To determine the variety and specificity of activity, the following factors were studied: phytohemagglutinin-induced LK that contained IFN-gamma (100 units/ml); purified IFN-gamma; human colony-stimulating factor 1 (CSF-1); and conditioned medium(a) (CM) from the human bladder carcinoma cell line 5637 and the hepatoma cell line SK-HEP. LK preparations contained no colony-stimulating activity, whereas CM from 5637 and SK-HEP both contained granulocyte-macrophage CSF (3000 to 4000 units/ml) but no IFN activity. IFN-gamma is the major immunoglobulin G Fc receptor-inducing species within lymphokine, since anti-interferon-gamma antibody inhibited most of this activity. Other sources of Fc receptor-inducing activity were CM from SK-HEP and 5637 cell lines. Human CSF-1 when tested up to 800 units/ml was inactive for Fc receptor induction. LK induced the chemotactic peptide receptor, but this induction was due to factors other than IFN-gamma as anti-IFN-gamma antibody did not inhibit the induction, and purified IFN-gamma at a dose equivalent to that found in LK (100 units/ml) had no activity in the assay. SK-HEP and 5637 CM had strong chemotactic peptide receptor-inducing activity, but human CSF-1 was inactive up to 800 units/ml. Peroxide production after stimulation with phorbol myristic acid could be induced by LK, LK with anti-IFN-gamma antibody, 5637, and SK-HEP treatment. IFN-gamma (100 units/ml) and CSF-1 (800 units/ml) were ineffective. Peroxide production was induced by IFN-gamma at concentrations above 1000 units/ml. The inducibility of several enzymatic activities was determined as additional measures of maturation. N-Acetylglucuronidase was induced, for example, by LK, IFN-gamma, 5637 CM, and phorbol myristic acid. Alkaline phosphatase was induced by LK, IFN-gamma, dexamethasone, and phorbol myristic acid. 1,25-Dihydroxycholecalciferol was also examined and could induce most of the maturational markers examined. The results demonstrate that non-IFN cytokines from several sources have profound differentiation-inducing effects on monoblast leukemia cells in a pattern different from that of IFN-gamma.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Distinct activities of interferon-gamma, lymphokine and cytokine differentiation-inducing factors acting on the human monoblastic leukemia cell line U937. 298 Nov 61

Activation of the c-myc proto-oncogene, in the form of DNA rearrangements that lead to constitutive expression, has been implicated in the genesis of a wide range of tumors. Therefore, it is of great interest to determine the influence of c-myc oncogene activation on cellular growth control, especially in primary cells. To facilitate the efficient transfer of an activated c-myc oncogene, we developed a mouse retrovirus that contains the c-myc protein-coding sequences and which can be transmitted in the presence of a Moloney murine leukemia virus helper or established as a helper-free stock with a retrovirus-packaging cell line. The virus can transform established lines of mouse fibroblasts to anchorage-independent growth; the transformed cells are tumorigenic in nude mice. However, the virus was not capable of inducing foci of transformed cells on confluent monolayers. In addition to studies on established cell lines, the effect of the c-myc retrovirus on primary cells was examined. Infection of bone marrow cells gave rise to partially transformed mononuclear phagocytes which were entirely dependent upon an exogenous supply of the monocyte-specific colony-stimulating factor CSF-1 for proliferation. Infection in vivo induced monocyte-macrophage tumors with a latency period of 8 to 10 weeks.
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PMID:A mouse c-myc retrovirus transforms established fibroblast lines in vitro and induces monocyte-macrophage tumors in vivo. 301 97

Since granulocyte/macrophage colony-stimulating factor (GM-CSF) has been reported to stimulate the proliferation of clonogenic leukemia cells from patients with acute non-lymphocytic leukemia in vitro, the expression of the GM-CSF gene in primary human leukemic blast cells was studied. T-cell-depleted mononuclear cells in freshly drawn peripheral blood from patients with acute non-lymphocytic leukemia (ANLL) were subjected to the study. The expression of the GM-CSF gene was detected by Northern blotting analysis using [32P]GM-CSF as a probe. The GM-CSF gene was expressed in two out of five cases examined. In both of the patients who showed GM-CSF expression, remission could not be achieved.
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PMID:Expression of the granulocyte/macrophage colony-stimulating factor gene in leukemic blast cells from patients with acute non-lymphocytic leukemia. 304 58

The production of interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 3 (IL-3) and granulocyte/macrophage colony stimulating factor (G/M-CSF) by preleukemic and leukemic spleen cells from Balb/c mice infected with Moloney leukemia virus (MoLV) was examined. During the development of the leukemia, the secretion of IL-1 and IL-2 significantly decreased, while the secretion of IL-3 and G/M CSF was not affected and was even enhanced. In addition, a 10 fold increase in the number of colony forming units in cultures (CFU-C) was found in the leukemic spleen indicating a shift in hematopoiesis from the bone marrow (BM) to the spleen. The low levels of IL-2 found in the conditioned medium of Concanavalin A (Con A) activated leukemic spleen cells could not result from active consumption of IL-2 by the cells, pointing to a genuine defect in IL-2 production. This failure of IL-2 secretion could be partially overcome by the addition of phorbol 12 beta-myristate 13 alpha-acetate (PMA) to the cells but not by the addition of IL-1. The defect in IL-2 production and the enhancement in IL-3 and G/M-CSF production may be of significance in the progression of preleukemic cells to autonomous malignant cells.
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PMID:Alterations in lymphokine secretion during leukemogenesis. 305 45

Stable expression of the 40-kDa transactivator protein (Tax) from the type I human T-cell leukemia virus (HTLV-I) in Jurkat T cells leads to the activation and sustained expression of certain cellular genes that are transiently induced during normal T-cell growth. Cellular genes induced by Tax include those encoding the alpha subunit of the high-affinity interleukin 2 receptor (Tac), interleukin 2, and granulocyte/macrophage colony-stimulating factor. Tax induction of the interleukin 2 gene is synergistically amplified by mitogens that augment cytoplasmic levels of calcium. These changes in the pattern of cellular gene expression reflect a specific action of Tax, as they are undetectable in isogenically matched control cell lines expressing antisense tax cDNA. The spectrum of cellular genes regulated by Tax appears to be restricted: several other T-cell genes, either inducibly or constitutively expressed, are unaffected by this viral protein. These cell lines constitutively expressing Tax provide valuable reagents to explore the molecular basis for Tax action and to delineate the full spectrum of cellular genes regulated by this retroviral gene product.
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PMID:Stable expression of the tax gene of type I human T-cell leukemia virus in human T cells activates specific cellular genes involved in growth. 305 51

The in vitro differentiation of multipotent stem cells in long-term marrow cultures can be blocked by treatment with agents that modify cholera toxin induced ADP-ribosylation of proteins. The latter agents also inhibit the growth and development of progenitor cells in soft gels in response to interleukin-3 but have little effect upon the development of progenitor cells that respond to the macrophage colony stimulating factor (CSF-1). Cholera toxin, in the same system, inhibits the development of CSF-1 responsive progenitor cells but has little effect on the development of cells that respond to IL-3. Similarly, progenitor cells that respond to IL-3 are relatively more resistant to pertussis toxin than cells that respond to CSF-1. These data indicate that ADP-ribosylation may be an important post-translational modification of regulatory proteins concerned with hemopoietic cell differentiation and growth in response to stromal cells or growth factors.
Leukemia 1988 Jan
PMID:The development of hemopoietic cells in response to stromal cells or growth factors is modified by agents that influence ADP-ribosylation. 312 9

THP-1 is an acute monocytic leukemia cell line which acquires phenotypic and functional monocytoid-like features following incubation with mezerein. The current study concerned the modulation of these features by rIFN gamma. rIFN gamma induces the time-dependent enhancement of HLA-DR expression in the presence or absence of mezerein but has no effect on the expression of Leu-M1, Leu-M2, or Leu-M3 antigens. CSF-1 production following mezerein activation was reduced by incubation in the presence of 10(3) and 10(4) units/ml rIFN gamma. This was confirmed through both biological assays with mouse bone marrow cells and an indirect ELISA. In contrast, the concentration of growth inhibitory activity in conditioned medium was increased by rIFN gamma. A small but significant increase in IL-1 beta concentration in conditioned medium was detected using a sensitive double-antibody ELISA and a radioimmunoassay. The results infer that the functional characteristics of this leukemia cell line are modulated by rIFN gamma in a manner qualitatively similar to that reported for IFN gamma treated normal monocytes.
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PMID:Regulation by interferon gamma of function in the acute monocytic leukemia cell line, THP-1. 312 95

There are 4 different normal myeloid hematopoietic cell growth-inducing proteins MGI-1 (CSF or IL-3) that induce normal precursor cells to multiply and form clones containing only macrophages (MGI-1M = M-CSF = CSF-1), only granulocytes (MGI-1G = G-CSF), both granulocytes and macrophages (MGI-1GM = GM-CSF), or granulocytes, macrophages, eosinophils, mast cells, megakaryocytes and erythroid cells (interleukin-3) (IL-3). There is another type of normal myeloid regulatory protein (MGI-2) with no MGI-1 (CSF or IL-3) activity which can induce differentiation of normal myeloid precursors and certain clones of myeloid leukemic cells. The present results with MGI-2 and pure recombinant MGI-1G, MGI-1GM and IL-3 have shown that different clones of myeloid leukemic cells can be induced to differentiate by different hematopoietic regulatory proteins. One type of leukemic clone is induced to differentiate to mature cells only by MGI-2 and is partially differentiated by MGI-1G, a second type is differentiated only by MGI-1GM or IL-3, and other workers have found a third type that is differentiated only by MGI-1G. The presence of surface receptors does not necessarily make leukemic cells differentiation-competent for these hematopoietic regulatory proteins. All 4 types of MGI-1 (CSF or IL-3) induce endogenous synthesis of MGI-2 in normal myeloid precursor cells. It is suggested that, in addition to their potential therapeutic effect on the development of normal hematopoietic cells, MGI-2, MGI-1G, MGI-1GM and IL-3 all have the potential for differentiation-directed therapy of leukemia in leukemic cells that can be differentiated by one of these normal hematopoietic regulatory proteins.
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PMID:Role of different normal hematopoietic regulatory proteins in the differentiation of myeloid leukemic cells. 325 7

A novel factor termed growth inhibitory (GI) factor, which specifically inhibits the growth of mouse monocytic leukemia cells including monocytic cell lines (Mm-A and J774.1) and other partially differentiated myeloid leukemic cells, has been purified from conditioned medium of some clones of mouse myeloblastic leukemia M1 cells. The procedure for purification of the GI factor included ammonium sulfate precipitation, CM-Sepharose CL-6B and Sephadex G-200 chromatographies, reverse-phase high-performance liquid chromatography on a C18 hydrophobic support, and high-performance liquid chromatography on a gel filtration column. The purified factor gave a single band of protein with a molecular weight of 25,000 on sodium dodecyl sulfate-polyacrylamide gel. A concentration of 8 X 10(-10) M GI factor was required for 50% inhibition of growth of Mm-A cells. On chromatofocusing, the GI activity was eluted with Polybuffer 96/acetic acid at pH 8.2-8.4. The purified GI factor markedly inhibited growth of mouse bone marrow cells stimulated by macrophage colony-stimulating factor. The GI factor appeared to be a unique cytokine unrelated to known cytokines such as the tumor necrosis factor, interferons, and oncostatin M.
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PMID:Purification of a novel growth inhibitory factor for partially differentiated myeloid leukemic cells. 328 39


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