Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibition of replicative DNA synthesis that follows DNA damage may be critical for avoiding genetic lesions that could contribute to cellular transformation. Exposure of ML-1 myeloblastic leukemia cells to nonlethal doses of the DNA damaging agents, gamma-irradiation or actinomycin D, causes a transient inhibition of replicative DNA synthesis via both G1 and G2 arrests. Levels of p53 protein in ML-1 cells and in proliferating normal bone marrow myeloid progenitor cells increase and decrease in temporal association with the G1 arrest. In contrast, the S-phase arrest of ML-1 cells caused by exposure to the anti-metabolite, cytosine arabinoside, which does not directly damage DNA, is not associated with a significant change in p53 protein levels. Caffeine treatment blocks both the G1 arrest and the induction of p53 protein after gamma-irradiation, thus suggesting that blocking the induction of p53 protein may contribute to the previously observed effects of caffeine on cell cycle changes after DNA damage. Unlike ML-1 cells and normal bone marrow myeloid progenitor cells, hematopoietic cells that either lack p53 gene expression or overexpress a mutant form of the p53 gene do not exhibit a G1 arrest after gamma-irradiation; however, the G2 arrest is unaffected by the status of the p53 gene. These results suggest a role for the wild-type p53 protein in the inhibition of DNA synthesis that follows DNA damage and thus suggest a new mechanism for how the loss of wild-type p53 might contribute to tumorigenesis.
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PMID:Participation of p53 protein in the cellular response to DNA damage. 2737 38

ML-1 human myeloblastic leukemia cells, suspended in RPMI-1640 medium, differentiated to monocyte or macrophage-like cells when either tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), or tetradecanoylphorbol acetate (TPA) was added prior to or simultaneously with fetal bovine serum (FBS). When FBS was applied first, and followed, after washing, by the cytokines or by TPA, maturation did not occur. A 77 kDa glycoprotein (DF77), isolated from human leukocyte-conditioned medium and present in FBS, was capable of replacing FBS for induction of differentiation. Thus, in this cell system, TNF-alpha, TGF-beta, and TPA acted as competence factors, whereas DF77 acted as the progression signal. Optimal competence was established after exposure of the cells to TPA or to either of the cytokines for approximately 2 or 30 min, respectively. After removal of the factors, competence was retained for approximately 3 hr before it declined. These results demonstrate that the initiation of ML-1 human myeloblastic leukemia cell differentiation relied upon the sequential and ordered input of competence and progression signals.
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PMID:Tumor necrosis factor-alpha, transforming growth factor-beta, and tetradecanoylphorbol acetate: competence factors for ML-1 human myeloblastic leukemia cell differentiation. 198 43

Effects of heptachlor, an organochlorine pesticide, on human myeloblastic leukemia ML-1 cells were determined. Similar to 12-O-tetradecanoylphorbol-13-acetate (TPA), a known tumor promoter, heptachlor induced cell adherence and formation of extended cytoplasmic pseudopodia in ML-1 cells. The growth of ML-1 was slightly stimulated by low concentrations (less than 30 nM) of heptachlor. A dose-responsive cell death was also observed when ML-1 cells were treated with heptachlor at concentrations greater than 80 microM. Examination by light microscopy of the cells treated with 80 microM heptachlor revealed a gradual appearance of differentiation characteristics in the culture. On Day 3 of the treatment, 41% of the cells remained unchanged as ML-1, 39% of the cells showed changes and apparent cell differentiation, and 20% of the cells were induced to differentiate to monocyte- or macrophage-like cell type. Electron microscopy also revealed cellular differentiation and the presence of monocyte- and macrophage-like cell types (22%) was confirmed by positive esterase staining.
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PMID:Induction of differentiation in human myeloblastic leukemia ML-1 cells by heptachlor, a chlorinated hydrocarbon insecticide. 203 53

Effects of transforming growth factor-beta 1 (TGF-beta 1), either alone or in combination with TNF, on the induction of differentiation of human myelogenous leukemic cell lines were examined. TGF-beta 1 alone induced differentiation of a human monocytic leukemia U-937 line into the cells with macrophage characteristics. When combined with TNF, TGF-beta 1 synergistically or additively induced differentiation associated properties. A human myeloblastic leukemia cell line, ML-1, differently responded to TGF-beta 1 in induction of differentiation. FcR activity and phagocytic activity induced by TNF were suppressed by TGF-beta 1. However, nitroblue tetrazolium reducing activity was synergistically induced by combinations of TGF-beta 1 and TNF. Scatchard analysis of TNF receptors indicated that the number of binding sites and dissociation constant of TNF for its receptors on U-937 or ML-1 cells were not changed by treatment with TGF-beta 1. Although IFN-gamma, IL-6, granulocyte CSF, and granulocyte-macrophage CSF-induced nitroblue tetrazolium reducing activity of U-937 cells, only IFN-gamma, and TNF induced it synergistically in combination with TGF-beta 1. Synergism between TGF-beta 1 and TNF was also observed in inhibition of growth of U-937 and ML-1 cells. Although TGF-beta 1 induction of differentiation of other monocytoid leukemic THP-1 cells was similar to that of U-937 cells, TGF-beta 1 only slightly induced differentiation of promyelocytic leukemic HL-60 cells, either alone or in combination with TNF. Our observations indicate that TGF-beta 1 strongly modulates differentiation and proliferation of human myelogenous leukemia cells, macrophage precursors.
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PMID:Effects of combinations of transforming growth factor-beta 1 and tumor necrosis factor on induction of differentiation of human myelogenous leukemic cell lines. 210 94

Proliferation and differentiation are coupled in normal cells and are aberrant in leukemia cells. The studies reported here were aimed at more effectively coupling proliferation-arrest and differentiation-induction in a human myeloblastic leukemia cell line (ML-1). This was accomplished by using reduced serum conditions in conjunction with a differentiation-inducing agent: cells were first incubated in reduced serum [0.3% fetal bovine serum (FBS)] instead of standard conditions (7.5% FBS) and, second, exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). The effects of this protocol were as follows: first, cell proliferation was slowed and cells accumulated in G0/G1 phase of the cell cycle; this occurred with only a minimal decrease in viability [to approximately 88-92% (0.3% FBS) from greater than or equal to 96% (7.5% FBS)]. Second, the induction of differentiation was accelerated; this allowed the time of exposure to TPA to be decreased. Acceleration of induction was very pronounced when cells were maintained in 0.3% FBS both before and during exposure to TPA, with TPA at concentrations above the minimum sufficient for induction but below those causing significant cytotoxicity; as little as 1 hour of TPA exposure resulted in near-maximal induction (approximately 80%) with this protocol, compared to the greater than or equal to 1 day required with previous standard protocols. In sum, conditions that slow ML-1 cell proliferation (0.3% FBS) enhance TPA-induced differentiation, substantially narrowing the time frame of induction; these conditions should be useful for studying the molecular mechanisms that underlie the induction process.
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PMID:Improved coupling between proliferation-arrest and differentiation-induction in ML-1 human myeloblastic leukemia cells. 227 61

ML-1 human myeloblastic leukemia cells are induced to differentiate to monocytes by conditioned medium (CM) derived from tetradecanoylphorbol acetate (TPA)-treated ML-1 cells. Antibodies to tumor necrosis factor (TNF) inhibited the differentiation-stimulating activity of CM, indicating that this activity is due to the presence of TNF in CM. TNF added to non-conditioned medium was as effective as CM in stimulating ML-1 cell differentiation. In the presence of a low (0.12 ng/ml) concentration of TPA, TNF-induced maturation was synergistically increased and Type I macrophages were formed. With higher (1-10 ng/ml) TPA concentrations, Type II macrophages were also obtained. As the TNF/TPA concentration increased, ML-1 cell differentiation was increasingly inhibited. Mature cells derived from ML-1 cells were found to secrete TNF at concentrations ranging from less than 2 U/ml to greater than 180 U/ml, the amount depending upon the number of cells and the stage of cell maturation. These results indicate that TNF participates in the regulation of precursor cell maturation. Low concentrations of TNF produced by small numbers of mature cells stimulate differentiation, whereas high concentrations of TNF generated by elevated numbers of macrophages inhibit the maturation process, possibly in combination with other cytokines. Because TNF serves as a competence factor for ML-1 cells, (Guan X.-P., Takuma T., Hromchak R. & Bloch A. (1990) Competence and progression in cell differentiation. Proc. Am. Assoc. Cancer Res. 31, 28.), the TNF-induced stimulation of differentiation depends additionally on the action of serum-contained differentiation-specific progression factors.
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PMID:A regulatory role for tumor necrosis factor (TNF) in ML-1 human myeloblastic leukemia cell maturation. 228 Jun 8

A series of monoclonal antibodies (mAb) were raised against nonlymphoid leukemic cell lines. Three of them have been characterized in detail. mAb H8 (IgG2), mAB U2 (IgG1), and mAb ML143 (IgM) were established with HEL, an erythroleukemia cell line, U937, a monocytoid (histiocytic) line, and ML-1, a myeloid cell line as immunogen, respectively. A 65 to 75 KD polypeptide was precipitated from monocytes by mAb H8, a 160 KD protein from monocytes by mAb U2, and two broad bands in the regions of 150 and 195 KD from granulocytes by mAb ML143. All three mAb stained peripheral blood monocytes and granulocytes, but not lymphocytes, platelets, and erythrocytes. The mAb reacted with immature myeloid cells in bone marrow, ranging from myeloblasts to mature myelomonocytic cells. They also were reactive with various nonlymphoid cell lines and leukemia of myelomonocytic origin. They did not react with B cell lines and B cell CLL cells. By complement-mediated cytolysis and/or an immune rosette method, antigens H8 and U2 were found to be expressed on the vast majority of CFU-GM (14 days) progenitors but not on BFU-E. Antigen ML143 was not expressed by either progenitor. Furthermore, ML143 antigen was found on T leukemia cell lines, a subpopulation of mitogen-activated T cells, and certain non-T/non-B ALL cells. This reactivity was not found with mAb H8 and U2. The relationship between these mAb and those reported are discussed. The possibility of using these mAb to obtain a markedly enriched CFU-GM progenitor population is also raised.
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PMID:Monoclonal antibodies against human myelomonocytic cells: detection of certain lineage-specific antigens on CFU-GM progenitor cells. 240 54

The effects of the tumor necrosis factor (TNF), and a second pleiotropic cytokine interferon-gamma (IFN), were examined in a line of human myeloblastic leukemia cells (ML-1). By itself, TNF causes ML-1 to differentiate along the monocytic pathway. The cells exhibit an increase in Fc receptors and acquire the morphological characteristics of maturing phenotype. They remain viable and continue to proliferate (at greater than or equal to 50% of the control growth rate) even with 10(2)-10(4) units/ml TNF. IFN alone has similar effects, causing an increase in Fc receptors but little cytotoxicity. In contrast to either cytokine alone, the combination of TNF plus IFN causes a cessation of proliferation and extensive cell death. Cytotoxicity occurs in a synergistic fashion; it requires the simultaneous presence of both cytokines, occurring with concurrent but not sequential exposure. These different responses, differentiation (TNF alone) and cytotoxicity (TNF + IFN), occur with a similar range of doses (approximately 10(2)-10(4) units/ml) and in a similar time frame (beginning on day 2). In other cell types, IFN can augment either the differentiation-inducing or the cytotoxic effect of TNF. In ML-1, the combined application of TNF plus IFN results in a shift from differentiation to cytotoxicity.
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PMID:Differentiation-inducing and cytotoxic effects of tumor necrosis factor and interferon-gamma in myeloblastic ML-1 cells. 250 96

N-Trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), a DNA nonbinding derivative of Adriamycin, was studied for its effect on the uptake of labeled nucleosides into human leukemia (ML-1) and lymphoma (P3HR-1) cells in culture. After preincubation with AD 143 at concentrations as low as 5.2 microM (ML-1) or 13 microM (P3HR-1), the ability of the cells to take up extracellular labeled nucleosides was decreased by more than 50%. Similar experiments with Escherichia coli cells showed that AD 143 at the same concentrations did not have any effect. Influx of [3H]thymidine or [3H]uridine was studied by centrifugation of the cells through phthalate oil mixture, and it was found that the influx of the labeled nucleosides was decreased after treatment of the cells with AD 143. An increase in the membrane fluidity was observed after treatment of the cells with AD 143, as revealed by electron paramagnetic resonance spectroscopy studies. These observations suggest that the decreased incorporation of [3H]thymidine and [3H]uridine into acid-precipitable material that we observed earlier in the AD 143-treated cells may in part be the result of the AD 143-induced alteration of cell membrane activities, which in turn causes an inhibition of nucleoside uptake.
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PMID:Nucleoside uptake and membrane fluidity studies on N-trifluoroacetyladriamycin-14-O-hemiadipate-treated human leukemia and lymphoma cells. 254 96

Prostaglandin E2 (PGE2) induced differentiation of human monoblastic leukemia U-937 cells into cells with macrophage characteristics. PGE2 synergistically increased the differentiation, of U-937, ML-1 and HL-60 cells when combined with TNF. PGE1 and PGF2 also induced differentiation of U-937 cells; however, PGD2, deoxy-delta 9,12-13, 14-dihydro-PGD2 (delta 12-PGJ2), and PGI2 did not induce differentiation, either alone or in combination with TNF. PGE2 changed the dissociation constant of TNF for its receptors on U-937 cells only marginally, but it approximately doubled the number of binding sites.
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PMID:Synergism of prostaglandin E2 plus TNF in induction of differentiation of human monocytoid leukemic U-937 cells. 254 32


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