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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Work over the past years and especially results of the past few years indicate that type-C viral or viral related genetic information exists in humans. 2. We do not know how this information entered humans or whether it causes disease, but it is of interest that the probes from the viruses used to detect this information are from the very same viruses which we find can affect growth and differentiation of some human hematopoietic cells. 3. The status of actual virus isolates from humans, though encouraging because of similarities of isolates from five different laboratories, remain very perplexing and so far have not been especially informative to human leukemogenesis. 4. In the near future we hope to clone in bacteria the viral related sequences detected in human DNA in order to more precisely determine their chemical and biological properties. The HL-60 system may also afford an opportunity to purify receptors for CSF. When CSF and other, perhaps more important, regulatory factors are purified, we would like to determine if they bind differently to leukemic and normal cells.
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PMID:Cellular and virological studies directed to the pathogenesis of the human myelogenous leukemias. 9 83

In vitro proliferative response of the blast cells from 21 AML patients to hematopoietic growth factors (IL-3, GM-CSF, G-CSF and MCSF) was investigated. Proliferation of AML cells in the majority of cases was induced or promoted by one or more CSFs, among which the stimulation of IL-3 was the most effective. Spontaneous proliferation of the blast cells was also observed in half of the cases and could be inhibited as well as promoted by some CSFs. It is suggested that in vitro proliferation of AML cells varies from patient to patient and that CSF plays important roles in leukemogenesis.
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PMID:[Effects of various recombinant human hematopoietic growth factors on proliferation of blast cells in acute myeloid leukemia in vitro]. 128 86

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.
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PMID:Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2. 145 74

Factor-independent mutants of hematopoietic cells, especially of multipotent cells, are valuable tools to identify genes that regulate stem cell proliferation and differentiation and thus may be important in leukemogenesis. Factor-independent mutants from both myeloid precursor and hematopoietic stem cell lines were isolated. The frequency of such mutants in a given cell population was one to two orders of magnitude lower for the multipotent cell line FDC-Pmix (3.6 x 10(-9)) than for the myeloid precursors, FDC-P1-M (1.7 x 10(-8)) and D35 (2.2 x 10(-7)). Analysis of these mutants revealed several mechanisms by which growth autonomy was obtained, either with or without direct contribution of growth factor gene activation. The molecular basis of spontaneous activation of the Multi-CSF (Interleukin3) gene was determined and compared to activation of the GM-CSF gene in a previous study. Multi-CSF gene activation in both precursor and stem cells was caused by the insertion of an intracisternal A particle (IAP) provirus. In two independent mutants of the D35 cell line, activation of the Multi-CSF or the GM-CSF gene was caused by almost identical IAPs with a 99% homology in the U3 and R region of the long terminal repeat. This result demonstrates that only one class of IAPs, or perhaps a single provirus, is involved in transposition and gene activation in a particular cell line. A unique example of anti-sense promotion from an IAP provirus in one Multi-CSF mutant underlines the versatility of these elements as natural insertional mutagens.
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PMID:Retrotransposons as mutagens in the induction of growth autonomy in hematopoietic cells. 217 39

32D C13(G) is an interleukin 3(IL3)-dependent non-tumorigenic murine hematopoietic cell line which undergoes terminal differentiation into granulocytes when exposed to granulocytic colony stimulating factor (G-CSF). Infections of 32D C13(G) cells with either Kirsten rat sarcoma virus or Balb murine sarcoma virus, both containing a v-ras oncogene, generates clones that can permanently grow in G-CSF without differentiation. 32D-Ki-ras cells show a heterogeneous morphology ranging from the promyelocytic to the myelocytic stage of differentiation, and express high levels of both myeloperoxidase (MPO) and lactoferrin (LF) mRNA. 32D-Ha-ras cells show a more immature phenotype and express MPO but no LF mRNA. The apparent differentiation block of both 32D Ki-ras and 32D Ha ras can be reversed by treatment with the chemical inducers retinoic acid, sodium butyrate or dimethylsulphoxide, which leads to terminal differentiation into granulocytes. When 32D-Ki-ras and 32D-Ha-ras cells are cultured in medium containing IL-3 they become adherent and express some monocyte-macrophage markers. Upon prolonged exposure to IL3, 32D-Ki-ras, but not 32D-Ha-ras, resume suspension growth. Both 32D-Ki-ras and 32D-Ha-ras rapidly die if grown in chemically defined medium in the absence of any growth factor and are non-tumorigenic in immunosuppressed mice. These findings indicate that ras activation may interfere with the normal response to growth and differentiation factors in cells of the granulocytic lineage. These alterations may represent a critical, although non-sufficient, step in leukemogenesis.
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PMID:Alteration of growth and differentiation factors response by Kirsten and Harvey sarcoma viruses in the IL-3-dependent murine hematopoietic cell line 32D C13(G). 246 24

Most primary myeloid leukemias are dependent for proliferative stimulation on the glycoprotein colony-stimulating factors. These agents are therefore mandatory co-factors in the development of myeloid leukemia. The CSFs also modify oncogene transcription, and in model leukemogenesis experiments GM-CSF has been shown to be a proto-oncogene. However, most evidence is against an autocrine hypothesis of myeloid leukemia based solely on CSF production by emerging leukemic cells. Because the CSFs also have differentiation commitment actions, they can induce differentiation in myeloid leukemic cells, and G-CSF in particular has an impressive capacity to suppress myeloid leukemic populations by this action. The antagonistic actions of the CSFs on myeloid leukemic cells make it difficult to predict whether they will prove to be useful agents in the management of myeloid leukemias.
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PMID:Hemopoietic growth factors and oncogenes in myeloid leukemia development. 332 69

The receptor for human granulocyte/macrophage colony-stimulating factor (hGMR) is composed of two subunits, alpha and beta, which are both required for high-affinity binding of the ligand. To examine the transforming potential of hGMR, we have transfected cDNAs encoding the receptor alpha and beta subunits into NIH 3T3 cells, which normally do not express GMRs. Introduction of the receptor subunits into these cells resulted in focal transformation, which was dependent on the presence of human granulocyte/macrophage colony-stimulating factor (hGM-CSF) in the culture medium. No transformation was observed when hGM-CSF was replaced with other growth factors such as human epidermal growth factor or human interleukin 3 or when cells were transfected with the alpha or beta subunit alone. Individual conditional transformants isolated after transfection expressed functional hGMRs, were susceptible to transformation by picomolar levels of the ligand, and were capable of anchorage-independent growth in soft agar in the presence but not in the absence of hGM-CSF. Biochemical analysis showed that treatment of these cells with hGM-CSF caused a rapid phosphorylation of the beta subunit and other cellular proteins on tyrosine residues, recapitulating some of the events that take place during GM-CSF signaling in myeloid cells. We conclude that coexpression of the alpha and beta subunits of hGMR in established murine fibroblasts is sufficient to reconstitute a functional receptor, which is capable of causing ligand-dependent transformation. The oncogenic potential of hGMR lends support to the hypothesis that its deregulated or abnormal expression may play a role in leukemogenesis.
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PMID:Ligand-dependent transformation by the receptor for human granulocyte/macrophage colony-stimulating factor and tyrosine phosphorylation of the receptor beta subunit. 768 16

Density-dependent cell proliferation and cluster formation are growth phenotypes frequently associated with leukemia cells. The secretion of autocrine growth factor, such as granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 1 (IL-1), has been implicated as one possible mechanism in leukemogenesis. In many cases, however, leukemia cells do not appear to produce autocrine growth stimulators. J6-1 is an established human myeloid leukemia cell line that exhibits both density-dependent and cluster-forming growth characteristics. The effect of direct cell-cell contact on J6-1 cell proliferation was investigated. We have isolated from J6-1 cells a membrane-bound factor (designated as MAF-J6-1) that promoted the colony formation by both J6-1 cells and mouse bone marrow CFU-GM. The growth-promoting activity of MAF-J6-1 can be neutralized by either anti-macrophage-CSF (M-CSF or CSF-1) or anti-MAF-J6-1 monoclonal antibodies (MAb), suggesting that MAF-J6-1 is related to M-CSF. Using an immunoblot analysis with anti-MAF-J6-1 MAb, the MW of this membrane-associated factor was estimated to be 80 kDa. Both antibodies also induced a modest growth inhibition on J6-1 cells in vitro. Similarly, addition of exogenous recombinant human M-CSF augmented the colony formation by J6-1 cells, an effect also neutralized by both antibodies. Using an in situ hybridization technique, J6-1 cells were found to express a high level of c-fms proto-oncogene, which encodes the receptor for the M-CSF. Taken together, our results suggest that the membrane-bound MAF-J6-1 promote J6-1 cell proliferation and cluster formation through a 'juxtacrine' mechanism.
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PMID:Enhancement of J6-1 human leukemic cell proliferation by cell-cell contact: role of an M-CSF-like membrane-associated growth factor MAF-J6-1. 796 11

Individuals with severe forms of congenital neutropenia suffer from recurrent infections. The therapeutic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to increase the neutrophil count is associated with fewer infections and an improved quality of life. However, the long-term effects of this new therapy are largely unknown. In particular, it is unclear if myeloid leukemia, a known complication of some forms of congenital neutropenia, will occur with increased frequency among patients who receive long-term treatment with hematopoietic growth factors. We report 13 patients with congenital disorders of myelopoiesis who developed leukemic transformation with either myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) and 1 who acquired a clonal cytogenetic abnormality without evidence of MDS or AML while receiving rhG-CSF. The bone marrows of 10 patients showed monosomy 7 and 5 had activating RAS mutations. These abnormalities were not detected in pretreatment bone marrows and cessation of rhG-CSF was not associated with either clinical improvement or cytogenetic remission. We conclude that patients with severe forms of congenital neutropenia are at relatively high risk of developing MDS and AML. The occurrence of monosomy 7 and RAS mutations in these cases suggests that the myeloid progenitors of some patients are genetically predisposed to malignant transformation. The relationship between therapeutic rhG-CSF and leukemogenesis in patients with severe chronic neutropenia is unclear.
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PMID:Monosomy 7 and activating RAS mutations accompany malignant transformation in patients with congenital neutropenia. 854 48

We have used a human GM-CSF-dependent hematopoietic cell line that responds to physiological concentrations of hGM-CSF to analyze a set of signaling events that occur in normal myelopoiesis and whose deregulation may lead to leukemogenesis. Stimulation of these cells with hGM-CSF induced the assembly of multimeric complexes that contained known and novel phosphotyrosyl proteins. One of the new proteins was a major phosphotyrosyl substrate of 76-85 kDa (p80) that was directly associated with the p85 subunit of phosphatidylinositol (PI) 3-kinase through the SH2 domains of p85. p80 also associated with the beta subunit of the activated hGM-CSF receptor, and assembly of this complex correlated with activation of PI 3-kinase. A second phosphotyrosyl protein we identified, p140, associated with the Shc and Grb2 adapter proteins by direct binding to a novel phosphotyrosine-interacting domain located at the N-terminus of Shc. and to the SH3 domains of Grb2, respectively. The Shc/p140/Grb2 complex was found to be constitutively activated in acute myeloid leukemia cells, indicating that activation of this pathway may be a necessary step in the development of some leukemias. The p80/p85/PI 3-kinase and the Shc/Grb2/p140 complexes were tightly associated with Src family kinases, which were prime candidates for phosphorylation of Shc, p80, p140 and other phosphotyrosyl substrates present in these complexes. Our studies suggest that p80 and p140 may link the hGM-CSF receptor to the PI 3-kinase and Shc/Grb2/ras signaling pathways, respectively, and that abnormal activation of hGM-CSF-dependent targets may play a role in leukemogenesis.
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PMID:Novel adapter proteins that link the human GM-CSF receptor to the phosphatidylino-sitol 3-kinase and Shc/Grb2/ras signaling pathways. 858 65


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