UMLS:C0023467 - FACTA Search

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Query: UMLS:C0023467 (acute myeloid leukemia)
35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF)-alpha and TNF-beta have multiple effects on human acute myeloid leukemia (AML) cells in vitro, including (1) synergistic stimulation of proliferation with interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and upregulation of interleukin-3 (IL-3) and GM-CSF receptors; (2) inhibition of granulocyte-CSF (G-CSF)-induced growth and rapid downmodulation of G-CSF receptors; and (3) induction of autocrine growth. Recently, two distinct TNF receptors (TNF-Rs), TNF-R(p55) and TNF-R(p75), have been identified. In this study, we show that both receptor types may be expressed by AML blasts. It has been investigated whether the different effects of TNF on AML blasts can be explained by differential activation of the distinct TNF-R structures. For this purpose, we used the monoclonal antibodies HTR-1 and HTR-9, specifically recognizing TNF-R(p55), and UTR-1, specific for TNF-R(p75). TNF-(alpha and -beta) mediated synergistic activation with IL-3/GM-CSF, upregulation of IL-3/GM-CSF receptors, inhibition of G-CSF-induced growth, and rapid downmodulation of G-CSF receptors exclusively result from activation of TNF-R(p55). In certain cases in which TNF-alpha, rather than TNF-beta, induces AML growth through an autocrine mechanism, both TNF-R(p55) and (p75) are involved. These data indicate that the variety of TNF responses observed in AML can only be partially explained by differential activation of the TNF-R(p55) and (p75) structures, and that TNF-R(p55) on AML blasts can transduce both positive (synergism with IL-3/GM-CSF) and negative regulatory signals (inhibition of G-CSF-induced proliferation) following TNF activation.
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PMID:Involvement of tumor necrosis factor (TNF) receptors p55 and p75 in TNF responses of acute myeloid leukemia blasts in vitro. 138 4

We carried out an in vitro study on the combined effects of three CSF (G-CSF, GM-CSF and IL-3) plus the cycle-specific chemotherapeutic drugs [cytosine arabinoside (Ara-C) and daunorubicin (DNR)] on the proliferation and cytotoxicity of blasts and clonogenic cells (CFU-AML) in the AML-193 cell line, in AML patients and in normal bone marrow CFU-GM. The number of surviving blasts and/or DNA synthesis in blasts treated with CSF plus Ara-C or DNR was greater than those treated without CSF in the AML-193 cell line, and in some AML patients. On the other hand, the Ara-C- and DNR-mediated cytotoxicity of CFU-AML was not abrogated by CSF in any instance, but rather, it was significantly enhanced by all the CSF in the majority of instances. Although the enhancement was clearer when Ara-C was used, compared with DNR, there were no significant differences among the enhancing effects of the CSF. Under the same culture conditions as those for CFU-AML, all of the CSF significantly enhanced the Ara-C-mediated cytotoxicity of day 7 normal CFU-GM, although to a lesser extent than in CFU-AML. However, none of the CSF significantly affected the Ara-C-mediated cytotoxicity of day 14 normal CFU-GM or the DNR-mediated cytotoxicity of day 7 or day 14 normal CFU-GM. These results suggest that in the selection of a strategy entailing combined use of cycle-specific drugs plus CSF to increase the antileukemic effectiveness of chemotherapy in AML, G-CSF is preferable to GM-CSF or IL-3, since it has fewer potential clinical side effects, and that, furthermore, DNR may be as useful as Ara-C.
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PMID:Comparative effects of G-CSF, GM-CSF and IL-3 on cytosine arabinoside- and daunorubicin-mediated cytotoxicity of acute myeloid leukemia cells and normal myeloid progenitors. 139 3

Ten patients with active acute myelogenous leukemia (AML) received either 13 cis retinoic acid (RA) + alpha interferon (IFN) or recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 3 days. Cell cycle measurements were performed before and at the conclusion of administration of the bioactive agent(s). The proliferative rate of the leukemia cells in vivo decreased in four of five patients receiving RA+IFN whereas in one patient proliferation accelerated. The proliferative rate of AML cells accelerated in three of the five patients who received rhGM-CSF and slowed in two patients. These data show that while the proliferative rate of AML cells can be altered in vivo, the effect produced by bioactive agents may be the opposite of the desired effect. Furthermore, the studies described here demonstrate the usefulness of marrow biopsies for measuring the percent S-phase cells and the importance of measuring the duration of S phase so that the effects of bioactive agents on the cell cycle time of the leukemia cells can be determined.
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PMID:Alteration of the proliferative rate of acute myelogenous leukemia cells in vivo in patients. 142 77

Loss of a whole chromosome 5 or deletion of 5q are recurring abnormalities in malignant myeloid neoplasms. Chromosomal loss or deletion are the hallmarks of tumour suppressor genes, suggesting that a gene(s) located on 5q may function as a leukaemia suppressor gene. To determine the location of genes on 5q that may be involved in myeloid leukaemogenesis, we examined the breakpoints of the del(5q) in a series of 117 patients with malignant myeloid diseases. By comparing the breakpoints, we identified a small segment of 5q, consisting of band 5q31, that was deleted in each patient. This segment has been termed the critical region. A striking number of genes encoding haematopoietic growth factors have been mapped within or adjacent to the critical region. These include the genes encoding CSF-2, IL-3, IL-4, IL-5 and IL-9. By using fluorescence in situ hybridization, we have refined the localization of these genes to 5q31.1. To facilitate the identification of a tumour suppressor gene on 5q, we are currently preparing a physical map of 5q31. With FISH analysis of a series of cosmid and phage clones, we identified a number of clones within 5q31. By hybridizing these probes to metaphase cells with a del(5q) involving proximal or distal breakpoints within 5q31, we have narrowed the critical region to a small segment of 5q31 containing eight of the cosmids. In addition, we found that the five growth factor genes are excluded from this region. We have used dual colour FISH to determine the order of these cosmids, the order of the known genes mapped to 5q23-33 and the relationship of these genes to the critical region. To date, mutations of these genes in leukaemia cells have not been identified. The clinical features of myeloid diseases associated with a del(5q) are variable (RA 5q- syndrome v. AML); thus, once the involved gene is identified, it will be important to determine whether the same gene is involved in both types of myeloid disorders.
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PMID:Deletions of chromosome 5 in malignant myeloid disorders. 145 Nov 9

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

The effects of in vitro pretreatment with benzene metabolites on colony-forming response of murine bone marrow cells stimulated with recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF) were examined. Pretreatment with hydroquinone (HQ) at concentrations ranging from picomolar to micromolar for 30 min resulted in a 1.5- to 4.6-fold enhancement in colonies formed in response to rGM-CSF that was due to an increase in granulocyte/macrophage colonies. The synergism equaled or exceeded that reported for the effects of interleukin 1, interleukin 3, or interleukin 6 with GM-CSF. Optimal enhancement was obtained with 1 microM HQ and was largely independent of the concentration of rGM-CSF. Pretreatment with other authentic benzene metabolites, phenol and catechol, and the putative metabolite trans, trans-muconaldehyde did not enhance growth factor response. Coadministration of phenol and HQ did not enhance the maximal rGM-CSF response obtained with HQ alone but shifted the optimal concentration to 100 pM. Synergism between HQ and rGM-CSF was observed with nonadherent bone marrow cells and lineage-depleted bone marrow cells, suggesting an intrinsic effect on recruitment of myeloid progenitor cells not normally responsive to rGM-CSF. Alterations in differentiation in a myeloid progenitor cell population may be of relevance in the pathogenesis of acute myelogenous leukemia secondary to drug or chemical exposure.
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PMID:Synergistic action of the benzene metabolite hydroquinone on myelopoietic stimulating activity of granulocyte/macrophage colony-stimulating factor in vitro. 157 Feb 88

We have examined the effect of a combined 24 h exposure to cytosine arabinoside (ara-C) and the protein kinase C activator bryostatin 1, either alone or in conjunction with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), on the clonogenic growth of 14 primary samples from acute myelogenous leukemia (AML) patients, as well as normal human committed and early hematopoietic progenitors. Incubation of blasts with 1 microM ara-C and 12.5 nM bryostatin 1(+/- 1.25 ng/ml rGM-CSF) resulted in a heterogeneous pattern of inhibitory effects toward primary leukemic colonies, ranging from 32-98%, and subadditive to synergistic drug interactions. However, exposure of blasts to ara-C and bryostatin 1, either with or without rGM-CSF, eliminated leukemic cell self-renewal in 80-93% of samples, and very substantially reduced growth in the remainder. Exposure of normal human bone marrow mononuclear cells to identical concentrations of ara-C and byostatin 1 permitted the survival of 23% of committed myeloid progenitors (granulocyte-macrophage colony-forming units), and greater than 50% when rGM-CSF was included. Finally, exposure of bone marrow populations highly enriched for progenitor cells (CD34+, DR-, CD71-) to ara-C and bryostatin 1 +/- rGM-CSF for 24 h led to minimal reductions (e.g. 10-15%) in the survival of early hematopoietic progenitors (high proliferative potential colony-forming cells). Together, these findings indicate that combined exposure in vitro to ara-C and bryostatin 1, both with and without rGM-CSF, effectively inhibits the growth of leukemic cells with self-renewal capacity, while sparing a significant fraction of normal committed and primitive hematopoietic progenitors.
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PMID:Effect of a combined exposure to cytosine arabinoside, bryostatin 1, and recombinant granulocyte-macrophage colony-stimulating factor on the clonogenic growth in vitro of normal and leukemic human hematopoietic progenitor cells. 159 8

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
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PMID:Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. 163 19

We designed two experiments using delayed stimulation by granulocyte/macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) with colony-type analysis in order to elucidate the characteristics of factor-dependent proliferation and differentiation of leukemic progenitor cells. Eight patients with acute myelogenous leukemia showing non-autonomous colony growth were selected. Three of the six cases showed that delayed addition of G-CSF to agar culture initiated by GM-CSF had no influence on the type and number of colonies; whereas, delayed addition of GM-CSF to G-CSF resulted in additional GM colonies. These findings were the same for normal bone marrow progenitors. In two cases, granulocytic colonies markedly increased with delayed addition of G-CSF to GM-CSF. Synergism occurred in one case where GM-CSF was used first. In the next experiment, regardless of whether CSF was used during the 48 hour preincubation, subsequent colony types were affected by the CSF used in agar culture. But colony numbers increased 1.5 fold in two of six cases by preincubation with GM-CSF, and 1.2 to 1.7 fold in all normal cases by preincubation with G-CSF. These results suggest that although there is a great heterogeneity in the response to CSF, some leukemic progenitors act like normal progenitors.
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PMID:Response of leukemic cells to the sequential combination of GM-CSF and G-CSF. 168 53

In this study we demonstrate that tumor necrosis factors (TNF alpha and TNF beta) are potent modulators of the in vitro proliferation of human AML cells. Blast cells from 11 cases of acute myeloblastic leukemia (AML) were incubated with recombinant TNF alpha or TNF beta in serum-free 3H-TdR uptake and colony culture systems in the presence or absence of recombinant interleukin-3 (IL-3), granulocyte macrophage colony-stimulating factor (GM-CSF), G-CSF, or M-CSF. Depending on the supplemented CSF, TNF could upregulate or suppress AML blast proliferation. Enhancement of AML growth by TNF was observed in the presence of IL-3 (in 9 of 11 cases in 3H-TdR assay; 6 of 9 cases in colony assay) and GM-CSF (in 8 of 11 cases in 3H-TdR assay; 4 of 9 cases in colony assay). In certain cases in which IL-3 or GM-CSF alone was unable to induce proliferative responses of AML cells, the simultaneous addition of TNF elicited colony growth and DNA synthesis suggesting a synergistic action between TNF and IL-3 or GM-CSF. In contrast, TNF suppressed G-CSF-induced growth (9 of 10 cases in 3H-TdR assay; 5 of 6 cases in colony assay). TNF could also stimulate DNA synthesis (in 2 of 11 cases) or colony formation (in 2 of 9 cases) in AML cultures without the addition of other growth factors. Experiments with neutralizing antibodies and specific radioimmunoassays for individual CSFs showed that the synergistic and antagonistic effects of TNF on AML growth could not be attributed to a release of one of these CSFs by the AML cells. The opposing consequence of exposure of AML blasts to TNF are of interest in view of our understanding of the pathophysiology of AML growth and the in vivo application of recombinant cytokines in AML patients.
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PMID:Modulation of colony stimulating factor-(CSF) dependent growth of acute myeloid leukemia by tumor necrosis factor. 168 38

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