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)

A sphingomyelin (SM)-signaling cycle has been described in human leukemia-derived HL-60 cells (Okazaki, T., Bell, R.M., and Hannun, Y.A. (1989) J. Biol. Chem. 264, 19076-19080). Activation of the cycle by tumor necrosis factor alpha (TNF alpha) occurs rapidly, with peak levels of approximately 30% SM hydrolysis observed within 45-60 min. The mechanisms by which TNF alpha induces this SM turnover remain largely unexplored. In this study, arachidonic acid (AA) was investigated as a potential mediator of TNF alpha effects on SM turnover. In HL-60 cells, 30 nM TNF alpha stimulated the release of AA within 5-10 min. In turn, AA stimulated SM hydrolysis and concomitant ceramide generation within 20 min of addition to cells. Other fatty acids, notably oleate, mimicked the effects of AA on SM hydrolysis, but the methyl ester and alcohol analogs of fatty acids were inactive. Diacylglycerol, a candidate mediator of TNF alpha responses, AA activated a cytosolic sphingomyelinase dose dependently, with 10-100 microM AA including 3-4-fold activation, thus suggesting a direct effect of AA on sphingomyelinase. Melittin, a potent phospholipase A2 activator, induced SM hydrolysis at concentrations as low as 35 nM. However, unlike AA, melittin was unable to stimulate sphingomyelinase activation in an in vitro assay system. Finally, exogenous addition of AA also produced antiproliferative effects reminiscent of ceramide effects. Thus, a role for the phospholipase A2/AA pathway in mediating TNF alpha induction of the SM cycle is supported by multiple lines of evidence. These studies begin to elucidate a mechanism of TNF alpha signaling and identify a close relationship between glycerophospholipid and sphingolipid signaling. AA, therefore, may be pivotal to understanding the sphingomyelin-signaling cascade.
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PMID:Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor alpha. 811 15

The clinical correlations of serum tumor necrosis factor alpha (TNF-alpha), a cytokine which can be released from leukemic blasts, has not been extensively studied. We have analyzed serum TNF-alpha in 20 ANLL, one CML-myeloblastic crisis, and 14 ALL adult patients by using a commercial ELISA kit. Sterile serum samples were taken on day 0, day 7, during remission and relapse with a mean follow-up period of 4.2 (1-19) months. After a median of 7 days following chemotherapy, serum TNF-alpha decreased both in responding ANLL (p = 0.004) and ALL (p > 0.05) but remained high in refractory leukemias. Values on day 7 were significantly different between responding and refractory patients in both ANLL (p = 0.0027) and ALL (p = 0.0099). At relapse, serum TNF-alpha increased starting at a median of 3 months preceding clinical symptoms in ANLL (p = 0.002). However, the relapse of ALL coincided with a slight increase which was not significant (p > 0.05). Together these findings indicate that serum TNF-alpha can be used as an early predictor of clinical response and relapse in ANLL.
Leukemia 1993 Nov
PMID:The clinical correlations of serum tumor necrosis factor-alpha in acute leukemias: a predictor of response and relapse? 823 Dec 45

We investigated the ultrastructural effects of recombinant tumor necrosis factor alpha (TNF) on primary leukemia cells of 8 patients (4 cases of acute myelogenous leukemia and 4 cases of chronic myelogenous leukemia) as well as on bone marrow cells of 1 normal control. The cells were kept in liquid culture for up to 92 h in the presence of up to 10,000 U/ml of recombinant human TNF without adding colony-stimulating factors. Under these conditions the concentration of viable leukemic cells decreased by 14 to 53%, compared to control cultures. In acute myelogenous leukemia, all cases to some degree developed an enlargement of mitochondria; in 2 cases prominent cytoplasmic processes, and in 2 cases cytoplasmic vacuoles were observed. In chronic myelogenous leukemia, an enlargement and deformation of all cell types was observed to varying degrees. In the normal bone marrow sample only minor cytoplasmic changes occurred. In all cultures apoptotic changes were rarely observed and--if present--were observed also in cultures without TNF. When the DNA of leukemic cells treated with TNF was separated on agarose, no fragments characteristic of apoptosis were visible. Our results demonstrate that TNF does not induce direct cytotoxicity or apoptosis in acute or chronic myeloid leukemias and are compatible with the notion that some leukemic cells may be activated or stimulated by TNF. The mitochondrion appears to be one of the primary targets of TNF. Electron microscopy is useful for monitoring the changes induced by TNF.
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PMID:Effects of tumor necrosis-factor on primary human leukemia cells: ultrastructural changes. 828 22

In order to clarify the role of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF alpha) in the pathogenesis of acute leukemia, IL-6 and TNF alpha level was determined in patients with various types of acute leukemia. In comparison with normal subjects, IL-6 activity was significantly elevated in patients with ALL and ANLL (P < 0.01) and TNF alpha level increased in patients with ANLL (P < 0.05). The effect of IL-6 and TNF alpha on leukemia cell in vitro was also observed. The results indicated that IL-6 can promote the proliferation of leukemia cells, while TNF alpha can inhibit proliferation of leukemia cell in vitro. It is suggested that abnormal level of TNF alpha and IL-6 in patients with acute leukemia is probably related to the pathogenesis of acute leukemia.
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PMID:[Tumor necrosis factor and interleukin 6 in acute leukemia]. 840 30

Acute myeloid leukemia (AML) cells are dependent for their survival and proliferation on hematopoietic growth factors. As tumor necrosis factor alpha (TNF alpha) can increase the proliferation of primary cultures of AML cells, we have investigated the effect of TNF alpha on the autocrine and/or paracrine growth control by one of the major AML growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF). First, a panel of AML cells were analysed with respect to their proliferative response to TNF alpha. We provide experimental evidence that TNF alpha induces both GM-CSF gene expression and up-regulation of high-affinity GM-CSF membrane receptor in TNF alpha-responsive cells. This effect is not restricted to the malignant phenotype, although it could account for the selective growth advantage of the leukemic clone over the normal cells upon TNF alpha stimulation.
Leukemia 1993 Oct
PMID:TNF alpha acts in synergy with GM-CSF to induce proliferation of acute myeloid leukemia cells by up-regulating the GM-CSF receptor and GM-CSF gene expression. 841 18

All-trans-retinoic (ATRA) treatment of patients with acute promyelocytic leukemia results in differentiation of the malignant cells and a high complete remission rate. ATRA treatment induced granulocytic differentiation in HL-60 cells as assessed by nitroblue tetrazolium (NBT) reduction, but had no effect on non-specific esterase (NSE) straining, as expected in cells maturing along the monocytic lineage. However, our results demonstrate that ATRA (0.1-10 microM) induces expression of the c-fms (monocyte colony-stimulating factor receptor) gene in HL-60 cells. This effect was detectable after 2 days and expression was maximal at 5 days. Similar results were obtained during treatment with cis-retinoic acid (CRA), hexamethylene bisacetamide (HMBA), or dimethyl sulfoxide (DMSO). The results also demonstrate that ATRA-induced c-fms expression is potentiated by exposure to tumor necrosis factor alpha (TNF alpha) or dibutyryl cyclic adenosine monophosphate (cAMP). The induction of c-fms transcripts by ATRA is associated with induction of M-CSF-binding ability, suggesting cell surface expression of the monocyte growth factor receptor. Our results indicate that retinoic acid can induce features of both monocytic and granulocytic differentiation in HL-60 cells.
Leukemia 1993 Mar
PMID:All-trans retinoic acid induces monocyte growth factor receptor (c-fms) gene expression in HL-60 leukemia cells. 844 50

Natural killer (NK) cells lyse autologous and allogeneic target cells even in the absence of major histocompatibility complex (MHC) class I antigens on the target cells. Recently, however, human allospecific NK cell clones have been generated that recognize at least five distinct specificities inherited recessively and controlled by genes linked to the MHC. Because the genetic specificity of these alloreactive NK cells in vitro appears analogous to that of in vivo NK cell-mediated murine hybrid resistance, i.e., the rejection of parental bone marrow in irradiated F1 animals, we tested the ability of human alloreactive NK clones to recognize allogeneic hematopoietic progenitor cells. NK cells from two specificity 1 alloreactive NK clones, ES9 and ES10, significantly and often completely suppressed colony formation by purified peripheral blood hematopoietic progenitor cells from specificity 1-susceptible donors, but had no significant effect on the cells of specificity 1-resistant donors. Activated polyclonal NK cells were less efficient than the NK clones in inhibiting colony formation and had a similar effect on cells from both specificity 1-susceptible and -resistant donors. The alloreactive NK clones produced cytokines with a suppressive effect on in vitro hematopoiesis, such as interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), when exposed to phytohemagglutinin blasts from specificity 1-susceptible, but not -resistant donors. However, the mechanism by which alloreactive NK cells inhibit colony formation is more consistent with a direct cytotoxic effect than with the production of inhibitory cytokines because antibodies (anti-IFN-gamma, alpha-TNF-alpha, and -lymphotoxin) that completely blocked the inhibition by polyclonal NK cells had only a minimal effect on the inhibition by the alloreactive clones. Moreover, the alloreactive clones were directly cytolytic in a 51Cr release assay against enriched preparations of peripheral blood progenitor cells from specificity 1-susceptible donors. These data indicate that the alloreactive NK cells are likely the human counterpart of the cells mediating murine hybrid resistance and that these cells might play clinically important roles in rejection or in graft-versus-leukemia reactions after allogeneic bone marrow transplantation.
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PMID:Regulation of hematopoiesis in vitro by alloreactive natural killer cell clones. 845 6

Bone marrow (BM) cells from a child with an immature (CD3-) acute T lymphoblastic leukemia (T-ALL) bearing no chromosomal abnormalities failed to grow in long-term culture in the presence or absence of recombinant human (rh) growth factors but could be engrafted in severe combined immunodeficient (SCID) mice and induced leukemia. The leukemic cells recovered from the animal tissues could be adapted to grow in vitro in the presence of rh interleukin-2 (IL-2) and give rise to a growth factor-dependent cell line designated TALL-107. This cell line expresses T-cell-specific mature markers (CD2, CD3/T-cell receptor [TCR] alpha beta, CD8, CD56), and its growth can be inhibited by IL-4 of all the cytokines tested. Similar to the original leukemic blasts, TALL-107 cells are clonal, have rearranged TCR-beta, gamma, and delta loci, and a normal 46 XY karyotype. However, unlike the patient's BM cells, the TALL-107 cell line displays potent tumoricidal activity that is not major histocompatibility complex restricted. The magnitude of mRNA expression of perforin and serine esterases and of lytic activity depends on the doses of IL-2 added. TALL-107 cells can also be triggered by CD3- and CD2-specific monoclonal antibodies (MoAbs) to mediate reverse tumor cell lysis. In addition, this cell line produces high levels of interferon gamma and tumor necrosis factor alpha on stimulation with anti-CD3 and/or anti-CD2 MoAb both in the presence or absence of IL-2. The overall data indicate that the SCID mouse is able to support the functional maturation and expansion of a cytotoxic T-cell subset from some types of T-ALL.
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PMID:Establishment of a karyotypically normal cytotoxic leukemic T-cell line from a T-ALL sample engrafted in SCID mice. 849 Jan 80

To ascertain whether the tumor cells can regulate the host immune systems through the production of the cytokines or their receptors, we examined the expressions of tumor necrosis factor alpha (TNF alpha), tumor necrosis factor beta (TNF beta), interleukin 2 (IL-2) and interleukin 2 receptor alpha chain (IL-2R alpha) on the human cancer cell lines by Northern blot analysis. We used K562 (leukemia cell line), MCF-7 (breast cancer cell line), LS180, HT29 (colon cancer cell lines), SH101 (gastric cancer cell line) and PH101 (pancreas cancer cell line). Expressions of TNF alpha, TNF beta and IL-2 mRNA were not detected in any of the tumor cell lines. However, 1.4 and 3.5 kilobases of the IL-2R alpha mRNA were expressed in the PH101 cells, but not in the other five cell lines. Furthermore, IL-2R alpha was detected on the cell surface of the PH101 cells by the flow-cytometric analysis with an anti-IL-2R alpha monoclonal antibody. Interestingly, the soluble IL-2R alpha (sIL-2R alpha) was found in the conditioned media obtained from the PH101 cell culture with a sandwich enzyme immunoassay. Moreover, the sIL-2R alpha secreted from the PH101 cells blocked the IL-2 dependent lymphocyte proliferation. These results indicate that the expression of IL-2R alpha on PH101 might suppress the IL-2 induced lymphocyte proliferation.
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PMID:The expression and biological activity of IL-2 receptor on a human pancreas cancer cell line. 850 43

The effectiveness of endogenous or exogenously administered colony-stimulating factors may be modulated by the presence of hematopoietic inhibitory molecules. Cytotoxic therapy may result in the induction of hematopoietic inhibitors contributing to prolonged myelosuppression, whereas preventing the induction of such inhibitors may accelerate multilineage recovery. Lisofylline [LSF; (R)-1-(5-hydroxyhexyl)-3,7, dimethyl-xanthine], inhibits the signaling and/or release of certain hematopoietic inhibitory molecules such as tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, transforming growth factor beta, and IFN-gamma. Treatment of murine bone marrow cells with the cytotoxic agent 5-fluorouracil (5-FU) results in the release of a nondialyzable inhibitor of progenitor (colony-forming unit-granulocyte macrophage; CFU-GM) proliferation. When murine bone marrow cells were treated with 5-FU plus LSF, release of this inhibitor of CFU-GM proliferation was blocked. Neutralizing antibody and Western blot analysis indicated that the inhibitor was TGF-beta. We tested the effect of LSF (100 mg/kg i.p., b.i.d.) on multilineage regeneration after high-dose 5-FU or thiotepa treatment in BALB/c mice. In 4 of 5 experiments, LSF significantly accelerated neutrophil recovery (P < or = 0.05, Wilcoxon paired-signed test). In addition, platelet, reticulocyte, and CFU-GM regeneration were significantly accelerated in mice treated with LSF compared to control mice (P < or = 0.05). LSF had no significant effects on the ability of 5-FU to kill hematopoietic progenitor cells, nor did LSF stimulate or inhibit proliferation of CFU-GM. LSF had no effect on chemotherapy-induced killing of tumor cells in vitro, nor on the antitumor activity of 5-FU or thiotepa in BALB/c mice implanted with P388 leukemia cells. Inhibition of hematopoietic inhibitor release may accelerate multilineage recovery after cytotoxic therapy and, as such, may represent an alternative or additional therapy to the use of positively acting lineage specific colony-stimulating factors.
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PMID:Lisofylline inhibits transforming growth factor beta release and enhances trilineage hematopoietic recovery after 5-fluorouracil treatment in mice. 854 48


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