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

Tumour necrosis factor (TNF) affects the growth of human leukaemic cells by different modes of action depending on the type of leukaemia involved. We have analysed the structure of TNF receptors on cells from different types of leukaemia, including acute lymphoblastic leukaemia (ALL), acute myeloblastic leukaemia (AML), chronic lymphocytic leukaemia (CLL), and chronic myelocytic leukaemia (CML) either in chronic phase (CML-CP) or blastic crisis (CML-BC). The affinity crosslinking technique showed the existence of TNF receptors on cells from all the leukaemic cases studied with similar receptor structures. The TNF receptor showed a molecular weight of 76 kD when examined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. In conclusion, we provide evidence for existence of TNF receptors on several types of human leukaemia cells with an apparent molecular weight of 76 kD. Apparently, the discrepancy of TNF actions on the leukaemic growth are not related to the structure of TNF receptors.
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PMID:Analysis of the TNF receptors on human leukaemia cells by affinity cross-linking. 132 64

Tumour necrosis factor (TNF) can act as an autocrine growth factor for hairy cell leukaemia (HCL) cells. The TNF produced by the malignant clone may also inhibit normal haematopoiesis thereby contributing to the cytopenias observed in patients with the disease. We have studied the effects of infusing a murine monoclonal anti-TNF antibody in three patients with HCL. In two patients receiving 0.5 mg of antibody/kg on alternate days for 12 d, the drug was well tolerated. The third patient received 2 mg/kg on alternate days and developed symptoms of serum sickness by day 9. In two patients with severe B-lymphocytopenia, circulating CD19 and CD20 positive, B-cells were restored to normal, the majority of which were negative for the HCL-associated marker CD11c. B-lymphocyte recovery was associated with a rise in serum immunoreactive IL-6 and with an early rise in immunoreactive TNF. These short courses of anti-TNF MAb treatment had modest effect on the tumour burden, producing a reduction in splenomegaly in one patient. Exploration of the effects of more prolonged administration of higher dose anti-TNF antibody will only be feasible when less immunogenic MAbs are available.
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PMID:Effects of anti-TNF monoclonal antibody infusion in patients with hairy cell leukaemia. 137 67

The mechanisms of paraneoplastic hypercalcemic syndromes are heterogeneous. Neoplastic hypercalcemia without bone metastatic disease is caused by parathyroid hormone related protein, whose action is comparable to parathyroid hormone. Growth transforming factors, platelet derived growth factor, tumor necrosis factors and interleukin 1 are also involved in humoral hypercalcemia of malignancy. In addition to these substances, hypercalcemia in bone metastatic disease may be related to PGE. Tumor necrosis factors and interleukin 1 play a major role in multiple myeloma as well as in Adult T cell Leukemia/Lymphoma where overproduction of vit D3 by lymphomatous cells can also be significant.
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PMID:[Hypercalcemia and neoplasms: recent advances in pathogenesis]. 229 Oct 7

Proto-oncogenes are thought to be involved in cellular differentiation and proliferation. Tumor necrosis factors (TNFs) are specific cytokines that have cytostatic and cytotoxic effects in vitro against a wide range of human tumor cells. We have previously demonstrated that recombinant TNFs (rTNFs) have an antiproliferative effect on certain human leukemic cell lines (HL-60, KBM3, KBM5) and no effect on others (K562). To study the possible role of the c-myc and c-myb oncogenes in this antiproliferative effect of TNF, we examined their expression in cell lines HL-60, KBM3, KBM5, and K562 before and after incubation with rTNF-alpha. Expression of c-myc and c-myb was elevated in all cell lines prior to incubation with rTNF-alpha. In the sensitive cell lines HL-60, KBM5, and KBM3 expression of c-myc and c-myb decreased rapidly 8-, 16-, and 4-fold, respectively, by 24 hr. K562 cells, insensitive to rTNF-alpha, exhibited no change in c-myc or c-myb expression over 24 hr. These studies demonstrated that down-regulation of c-myc and c-myb expression were associated with antiproliferative effects of rTNF-alpha on these cell lines.
Leukemia 1988 Nov
PMID:Suppression of c-myc and c-myb expression in myeloid cell lines treated with recombinant tumor necrosis factor-alpha. 305 50

Cells of the human myelomonocytic line RC-2A can be induced to differentiate towards mature monocytes by culture in the presence of phytohaemagglutinin-treated lymphocyte conditioned medium (Lyons and Ashman, Leukemia Res. 11, 797, 1987). We have now examined the effect on RC-2A cells of some (recombinant) cytokines which might be present in conditioned medium. Gamma interferon most closely mimicked the effect of conditioned medium in inducing clonogenic suppression and the induction of monocytic maturation over 7 days of culture. Granulocyte colony stimulating factor induced enhancement of proliferation followed by clonogenic suppression, while granulocyte-macrophage colony stimulating factor had a purely stimulatory effect on proliferation over a 7-day period. Tumour necrosis factor alpha failed to affect cell proliferation or to induce characteristic monocytic differentiation, but did increase the expression of C3bi receptors. We conclude that RC-2A cells have receptors for all four cytokines studied, and that gamma interferon is a major differentiation-inducing stimulus for these cells.
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PMID:The effect of recombinant cytokines on the proliferative potential and phenotype of cells of the human myelomonocytic leukaemia line, RC-2A. 318 82

Tumour necrosis factor (TNF) induces the lysis of many malignant cells in vitro and regression of some tumours in vivo. However, TNF is also a growth factor for normal fibroblasts, T cells and B cells and we have recently shown that TNF can also act as a growth factor for chronic B cell neoplasms, including hairy cell leukaemia and B-CLL. In these cells it promotes proto-oncogene expression, RNA and DNA synthesis and increases overall cell survival. Stimulation appears to be autocrine in nature since exposure of the neoplastic cells to recombinant TNF protein induces the corresponding messenger RNA and synthesis of the protein itself. TNF induced proto-oncogene expression and DNA synthesis occur over a substantially longer time period than when the cells are stimulated with agents such as TPA and Calcium ionophore (2), but we have no evidence that the delay represents the time taken to generate TNF dependent secondary cytokines such as IL-1 and IL6. Alpha interferon opposes TNF mediated activation and our recent data indicate that this effect is independent of alpha interferon down regulation of TNF receptors. It appears to be related instead to a decreased accumulation of TNF mRNA which occurs contemporaneously with an alpha interferon induced rise in 2-5 A synthetase. If TNF dependent growth is important for the survival of B-CLL cells, then agents which mimic alpha interferon or which block TNF induced autocrine growth would be predicted to be of therapeutic benefit.
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PMID:Effects of tumour necrosis factor and alpha interferon on chronic B cell malignancies. 326 1

Malignant B lymphocytes from patients with B-chronic lymphocytic leukaemia (B-CLL) or hairy cell leukemia (HCL) are refractory in vitro to mitogenic stimulation by several agents which trigger proliferation of normal B cells. Tumour necrosis factor (TNF) is a growth factor for these malignant cells, although the proliferative response is usually small. TNF regulates some of its cellular responses via induction of the transcription factors NF kappa B and AP-1 (jun/fos). The induction of NF kappa B by TNF is mediated via a novel signalling pathway involving the generation of reactive oxidative intermediates. Induction of jun and fos proteins (polypeptide components of AP-1) are mediated via pathways involving protein kinase C and the protein kinase encoded by the raf proto-oncogene. Here we have used an electrophoretic mobility shift assay to show that TNF induced NF kappa B in malignant cells isolated from 3/3 HCL and 15/15 B-CLL patients. By contrast, phorbol myristate acetate (PMA), a direct activator of protein kinase C, failed to activate this transcription factor in 1/1 HCL and 5/5 B-CLL isolates. The induction of jun and fos proteins (as detected by Western blot analysis) showed greater heterogeneity. Nuclear jun was induced by TNF in 5/12 chronic B cell leukaemia isolates. PMA induced this protein in 4/5 samples. Nuclear fos was induced by TNF in only 2/12 isolates and by PMA in 2/5. The data suggest that the pathways for the activation of jun and fos by TNF are defective in some B-CLL and HCL cells and that these defects may be heterogeneous. The induction of AP-1 is crucial in securing the mitogenic response to TNF. It is therefore plausible that these lesions may contribute to the refractory nature of B-CLL and HCL cells to proliferative stimuli in vitro.
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PMID:Regulation of transcription factors NF kappa B and AP-1 following tumour necrosis factor-alpha treatment of cells from chronic B cell leukaemia patients. 804 32

We have shown that therapy of AML patients in second remission with continuous infusion of IL-2 resulted in generation of cytotoxic lymphocytes in peripheral blood and bone marrow. However, these lymphocytes mediated cytotoxicity only against tumor cell lines, and not against AML blasts. Additional in vitro activation with higher dose of IL-2 was necessary for induction of AML blast oncolysis. This indicates that the concomitant treatment with continuous and periodic bolus IL-2 infusion may be necessary, to achieve higher levels of IL-2 and subsequently, more potent lymphocyte activation. Alternatively, it may not be possible to induce optimal antileukemia response in vivo with tolerable doses of IL-2, and the adoptive therapy with in vitro supremely activated lymphocytes may represent an option. In this article, we discuss several approaches to the supreme activation of cytotoxic lymphocytes against highly resistant AML blasts and their possibilities in leukemia therapy.
Leukemia 1993 Aug
PMID:Recent approaches to induction of cytotoxic lymphocytes against leukemia. 836 Dec 37

Transplantation of bone marrow autografts activated by culture in interleukin-2 (IL-2) followed by administration of IL-2 represents a novel approach in an attempt to combine ex vivo purging and post-transplant in vivo immunotherapy, and initial clinical results have suggested its feasibility. To further characterize the mechanism of the in vitro anti-leukemia effect, fresh bone marrow from normal donors and from patients with acute myelogenous leukemia (AML) in remission was cultured for 6 days in the absence or presence of IL-2 (1000 IU/ml). Proliferation of CD3, CD8, CD14, and CD56 cells was determined by direct immunofluorescence using flow cytometry. Predominantly T-lymphocytes (CD3+) and to a lesser extent CD56+ natural killer (NK) cells proliferate in 6-day marrow cultures in IL-2. Fresh bone marrow cells have no measurable NK activity when tested against K562 and Daudi target cell lines in a 4 h chromium-51 release assay, and it requires at least 6 days of culture in IL-2 to develop optimal cytotoxic activity. Cytokines released in the supernatants of these cultures were measured by immuno- and bioassays. Tumour necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and IL-6 were found to be produced in significant amounts by marrow mononuclear cells during culture in IL-2. Even without IL-2 present, concentrations of these cytokines were increased in 6-day marrow cultures. In contrast, IL-3, IL-7, granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) were below the level of detection of the immunoassay, a result that could be confirmed for GM-CSF and IL-3 by bioassay. The data suggest that culture of marrow from normal donors as well as from patients with AML obtained in remission can generate anti-leukemia effector mechanisms which are non-crossreactive with chemo- and radiotherapy and may contribute to effective ex vivo purging of residual leukemic cells. The transplantation of such IL-2 'primed' marrow may also contribute to an in vivo graft-versus-leukemia effect.
Leukemia 1993 Sep
PMID:Culture of normal and leukemic bone marrow in interleukin-2: analysis of cell activation, cell proliferation, and cytokine production. 837 89

Tumour necrosis factor (TNF)-alpha exerts multiple effects on human acute myeloblastic leukaemia (AML) cells in vitro, including (1) synergistic stimulation of proliferation with interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF); (2) inhibition of granulocyte-CSF (G-CSF) and stem cell factor (SCF)-induced growth; (3) suppression of multiplication of clonogenic leukaemic cells; (4) induction of autocrine growth. Recently, two distinct TNF receptors (TNF-Rs), TNF-Rp55 and TNF-Rp75, have been identified. In this study we show that both receptors are expressed on freshly isolated AML blasts, with p75 being the predominant TNF-receptor type. This study investigates the roles of these two receptors in TNF-alpha-driven growth regulation of AML blasts in vitro. Using a receptor-specific antibody, it is shown that both receptor types participate in TNF-alpha-mediated stimulation of GM-CSF/IL-3-induced proliferation and in TNF-alpha-induced autocrine growth. In contrast, the TNF-alpha-triggered growth inhibition (antiproliferation) and the potent suppression of G-CSF- and SCF-induced proliferation exclusively result from activation of TNF-Rp55. Taken together, these results suggest that the proliferative effects of TNF-alpha on AML blasts are mediated through both p55 and p75 TNF receptors, whereas the TNF-alpha-signalled growth inhibition is exclusively transduced via TNF-Rp55.
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PMID:Expression and role in growth regulation of tumour necrosis factor receptors p55 and p75 in acute myeloblastic leukaemia cells. 856 81


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