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)

Homeostasis of human B cell development is maintained by a complex network of cytoplasmic and surface expressed molecules. Abnormalities in this process may result in the expansion of malignant B cell precursors in B lineage acute lymphoblastic leukaemia (ALL). ALL cells share surface antigens with normal early precursor B cells. We have studied here the role of Fas/APO-1 (CD95) antigen on leukaemic precursor B cell line growth and survival, and the modulation of its effects by signals involved in normal early B cell development. Four ALL cell lines representative of the early steps of B cell differentiation are shown to express surface Fas/APO-1 (CD95) antigen and to undergo apoptosis in the presence of anti-Fas cross-linking antibodies. This effect is strongly enhanced when pre-B, but not pro-B cells, are pretreated with IL-7 but not with IL-2, IL-3, IL-4 or IL-10. Furthermore, pre-B cell death induced by anti-Fas antibodies in combination with IL-7 is increased upon pre-B receptor but not CD19 cross-linking. Bcl-2 and Bax protein expression is not influenced by IL-7 or pre-BR stimulation in either pro-B or pre-B cell lines. These results indicate that signals involved in normal early B cell development can modulate the Fas (CD95)-mediated apoptosis of leukaemic precursor B cells.
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PMID:IL-7 sensitizes human pre-B cells but not pro-B cells to Fas/APO-1 (CD95)-mediated apoptosis. 936 21

The transcription factor NF-kappaB plays an important role in the regulated expression of cytokines in human monocytes. A p100 subunit of NF-kappaB has IkappaB-like properties by sequestering the p65 transactivating subunit in the cytosol of cells. In transient transfection assays we demonstrated that p100 has an inhibitory effect on the NF-kappaB-dependent IL-6 promoter activity. In view of this finding, we studied the regulation of the p100 subunit in human monocytes in response to LPS, the inflammatory cytokines IL-1beta and TNF-alpha and lymphokines. The results demonstrate that LPS, IL-1beta, and TNF-alpha induce p100 expression at mRNA and protein level while IFN-gamma, IL-3 and IL-4/IL-10 have no effect. The induction of p100 expression was shown to be mediated by a two-fold increase in the p100 transcription rate and a two-fold increase in p100 mRNA stability. Furthermore the p100 mediated upregulation was dependent on a tyrosine kinase dependent pathway rather than the protein kinase C pathway. NF-kappaB is a complex of either p50 homodimers or a p50/p65 heterodimer. The latter is known to strongly autoregulate p100 transcription. We therefore examined the composition of NF-kappaB induced by LPS vs the different lymphokines. LPS-induced NF-kappaB showed a distinct p65 supershift whereas the composition of NF-kappaB induced by different lymphokines did not show a change in p65. We conclude that the p100 subunit of the transcription factor NF-kappaB is induced by different inflammatory mediators while lymphokines fail to induce p100 expression which may be caused by the induction of NF-kappaB predominantly consisting of p50 homodimers.
Leukemia 1998 Mar
PMID:Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines. 952 31

Human malignant cells are targeted by homologous complement C3b if they express M161Ag, a 43-kDa protein with C3-activating property. cDNA of M161Ag cloned from human leukemia cell lines predicted M161Ag as a novel secretory protein comprised of 428 amino acids including 5 amino acids encoded by TGA codons (Matsumoto M., Takeda, J., Inoue, N., Hara, T., Hatanaka, M., Takahashi, K., Nagasawa, S., Akedo, H., and Seya, T. (1997) Nat. Med. 3, 1266-1270), although the origin of this gene was obscure. Here we clarified this point through genomic and biochemical analysis: 1) 5'-UT and genomic sequences represented the prokaryote promoter and ribosomal binding site; 2) the TGA codons in M161Ag cDNA were translated not into selenocysteines but into tryptophans; 3) M161Ag anchored onto the membrane secondary to its N-terminal palmitoylation like prokaryote lipoproteins; 4) genomic and cDNA clones of M161Ag were highly homologous to Mycoplasma fermentans gene encoding P48, a monocytic differentiation/activation factor, recently released in the data base, although the resultant proteins were different in the amino acid sequences. Additionally, purified soluble M161Ag efficiently provoked IL-1beta, tumor necrosis factor alpha, and IL-6 like P48, and further IL-10 and IL-12 in human peripheral blood monocytes. Thus, M161Ag originates from M. fermentans, and latently infected M. fermentans allows human cells to produce M161Ag. The liberated protein serves as a potent modulator of innate and cellular immune responses via its complement-activating and cytokine-producing activities.
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PMID:Structural and functional properties of complement-activating protein M161Ag, a Mycoplasma fermentans gene product that induces cytokine production by human monocytes. 957 96

T lymphocytes are important both for the host defence against infections and probably also as antileukaemic effector cells in patients with acute leukaemia. To investigate the T lymphocyte cytokine repertoire of clonogenic T lymphocytes, CD4+ and CD8+ T lymphocyte clones were prepared from acute leukaemia patients with chemotherapy-induced cytopenia (leucocytes <0.5x 10(9)/l). A majority of both CD4+ and CD8+ clones secreted detectable interleukin-2 (IL-2), IL-10, IL-13, granulocyte/macrophage-colony-stimulating factor and interferon gamma (IFNgamma) in response to phytohaemagglutinin + accessory cells (Epstein-Barr-virus-transformed B cell line, 80-Gy-irradiated). The CD4+ clones showed significantly higher levels of IL-10 secretion than the CD8+ clones. Decreased levels of IL-2, IL-13 and IFNgamma were observed when acute myelogenous leukaemia (AML) blasts were used instead of cells from the B cell line as accessory cells during phytohaemagglutinin activation, but the differences in IL-13 and IFNgamma levels were reversed by addition of exogenous IL-2. On the basis of these results we conclude: (i) the remaining clonogenic T lymphocytes derived from acute leukaemia patients with therapy-induced leucopenia can respond to activation with a broad cytokine response, and T-cell-derived cytokines may then contribute to cytokine responses during complicating infections in these patients; (ii) although T cells can modulate AML blast functions and mediate antileukaemic effects, the leukaemia blasts will also modulate T cell functions and alter the cytokine profile of activated T lymphocytes.
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PMID:Cellular immune responses in acute leukaemia patients with severe chemotherapy-induced leucopenia; characterization of the cytokine repertoire of clonogenic T cells. 967 Nov 45

Telomerase activity is upregulated in activated and malignant lymphocytes. We studied the correlation of telomerase and IL-10 to leukemia transformation in the NZB mouse model of human chronic lymphocytic leukemia (CLL). Telomerase levels increased from early to late leukemic stages, likewise IL-10 gene expression levels increased with the leukemic progression. The inverse relationship of telomerase and IL-10 levels to the survival of NZB mice was also established. Our data suggested that telomerase and IL-10 were involved in transformation in the murine model of CLL and the detection of telomerase activities might be of value in the prediction of CLL progression.
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PMID:The correlation of telomerase and IL-10 with leukemia transformation in a mouse model of chronic lymphocytic leukemia (CLL). 967 17

Numerous studies have shown spontaneous IL-10 gene expression and synthesis in a variety of peripheral blood or bone marrow-derived leukemic cells. These include B-cells derived from various lymphoproliferative disorders. Since little is known regarding IL-10 expression in leukemic T-cells, we examined clinical specimens of patients with adult T-cell leukemia (ATL) for IL-10 expression. Sera from ATL patients show increased levels of IL-10 when compared with sera from healthy donors. IL-10 is constitutively produced by ATL cells and also by human T-cell leukemia virus type I (HTLV-I)-infected cell lines. It is thought that HTLV-I infection induces gene expression for IL-10. In this review, a transcriptional regulation of IL-10 gene expression by HTLV-I Tax and the possible role of the NF-kappaB pathway are described.
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PMID:Interleukin-10 gene expression and adult T-cell leukemia. 968 22

Human ovarian adenocarcinoma cells N.1 secrete an autocrine activity that stimulates active cell death under serum-reduced conditions. To substitute the autocrine activity by a single physiological component, 28 cytokines, growth factors and biomodulators were tested [interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-11, stem cell factor (SCF), platelet-derived growth factor (PDGF), acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1), IGF-2, insulin, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), oncostatin, RANTES (regulated on activation normal T cell expressed and secreted), angiogenin, leukaemia inhibitory factor (LIF), erythropoietin (EPO), interferon alpha (INF-alpha), INF-gamma, transferrin, tumour necrosis factor alpha (TNF-alpha, TNF-beta and bovine serum albumin for control reasons]. In these experiments, only TNF-alpha and TNF-beta rapidly induced apoptosis. TNF-alpha and TNF-receptor 1 were expressed by N.1 cells, and the secretion of TNF-alpha was verified by enzyme-linked immunosorbent assay (ELISA). Autocrine factor-triggered apoptosis was inhibited when conditioned supernatant was preincubated with anti-TNF-alpha antibody. These findings suggested that the apoptosis-inducing component of the N.1 autocrine activity was TNF-alpha. In the presence of antisense c-myc oligonucleotides, induction of cell death by autocrine factor was partly inhibited. Autocrine factor and TNF-alpha stimulated transcription of the invasiveness-related protease plasminogen activator/urokinase mRNA (upa) with similar kinetics. When N.1 cells were exposed to purified plasminogen activator/urokinase protein (uPA), cell matrix contact was disrupted. Thus, uPA might serve a physiological role during TNF-induced apoptosis by affecting the interactions between cells and the basal membrane, thereby facilitating anoikis. This mechanistic study, which was restricted to a single human ovarian carcinoma model cell line (N.1), provides evidence that N.1 maintains the capacity to undergo c-myc-dependent apoptosis by the TNF-TNF-receptor pathway, and no additional pharmacological stimuli for induction of apoptosis are required.
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PMID:Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). 976 76

Our recent work has shown that theophylline which inhibits intracellular cyclic adenosine monophosphate (cAMP) degradation is able to kill chronic lymphocytic leukemia (CLL) cells in vitro and synergizes in vitro and in vivo with chlorambucil. In order to test the hypothesis that theophylline works through an indirect increase in cAMP, we have investigated the role of several molecules on B-CLL cells from 20 patients. Direct cAMP inducers such as dibutyryl-cAMP (db-cAMP), prostaglandin-E2 (PGE2) and forskolin induced moderate apoptosis but extremely high levels of intracellular cAMP. By contrast theophylline was highly apoptotic but did not synergize with cAMP inducers. Apoptosis was completely reversed by a cAMP antagonist when induced by PGE2 or forskolin, but was only partially antagonized when induced by theophylline. Since CD38+ CLL cells are more sensitive to apoptosis and since CD38 is enhanced by cAMP inducing agents its expression was investigated. In our hands CD38 was not induced by the above pharmacological compounds. Exogenous IL-10 has been shown to induce CLL cell death; however, apoptosis following treatment with theophylline or cAMP inducers could not be ascribed to endogenous production of IL-10. This ruled out the involvement of cytokines or of an activation or differentiation process in apoptosis. Altogether our data show that an increase in intracellular cAMP mediates apoptosis in vitro but accounts only partly for theophylline-mediated apoptosis.
Leukemia 1999 Jan
PMID:Theophylline-induced B-CLL apoptosis is partly dependent on cyclic AMP production but independent of CD38 expression and endogenous IL-10 production. 1004 64

Cyclosporin A (CsA) has been used clinically to induce graft-versus-host disease following autologous bone marrow transplantation in an attempt to destroy residual leukemia cells and reduce relapse. To analyze the antitumor potential of murine syngeneic graft-versus-host disease (SGVHD), C3H/HeN mice were lethally irradiated, reconstituted with T cell-depleted syngeneic bone marrow (ATBM) and treated with CsA for 21 days. Graft-versus-leukemia activity was assessed by challenging groups of olive oil-treated control ATBM (OO-ATBM) and CsA-treated (CsA-ATBM) mice 1 week after CsA therapy with graded doses of the syngeneic 38C13 B cell lymphoma. Following CsA treatment, up to 70% of CsA-ATBM developed SGVHD and more than 70% of the animals injected with 500 38C13 cells exhibited long-term survival (MST >80 days). In contrast, none of the OO-ATBM control mice developed SGVHD, and more than 75% of these mice died following injection of 500 38C13 tumor cells (MST = 34 days). Long-term survivors were not resistant to tumor challenge suggesting that tumor-specific immunity did not develop. Finally, class II negative 38C13 cells cultured in IL-4 or IL-10 were not inducible for MHC class II molecules, demonstrating that class II-independent antitumor mechanisms exist in SGVHD mice.
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PMID:Rejection of an MHC class II negative tumor following induction of murine syngeneic graft-versus-host disease. 1010 May 80

Primary effusion lymphoma (PEL) is a new lymphoma entity occurring predominantly, but not exclusively in HIV+ patients with acquired immunodeficiency syndrome (AIDS). PEL grows exclusively in body cavities as serous lymphomatous effusion without evidence of mass disease or dissemination. The cells are infected with the newly discovered human herpesvirus-8 (HHV-8), often accompanied by co-infection with Epstein-Barr virus (EBV). Several lymphoma cell lines have been established from patients with AIDS- and non-AIDS-associated PEL. Given their phenotypical relationship to plasma cells, several cytokines may be important for growth and survival of PEL cells. We investigated the spectrum of cytokines produced by nine HHV-8+ PEL cell lines, in comparison with five Burkitt lymphoma, seven other B non-Hodgkin's lymphoma (B-NHL) and seven multiple myeloma-derived cell lines. In addition, we tested the response of the PEL cells to selected cytokines and the effects of neutralizing anti-cytokine and anti-cytokine receptor antibodies. Using specific ELISAs, PEL cell lines were found to produce large amounts of interleukin-6 (IL-6; 10-5000 pg/ml), IL-6 soluble receptor (IL-6sR; 30-600 pg/ml), IL-10 (600-80,000 pg/ml) and oncostatin M (OSM; 50-80 pg/ml) which in most cases were significantly higher than the levels produced by the Burkitt, B-NHL or myeloma cell lines; on the contrary, PEL cell lines did not elaborate significant levels of macrophage inhibitory protein (MIP-1alpha) and leukemia inhibitory factor (LIF). However, the levels of MIP-1alpha were increased 10- to 100-fold by treatment with phorbol ester TPA. PEL cell lines did not respond proliferatively to IL-6, IL-10, IL-11, LIF, MIP-1alpha, or OSM. Incubation with IL-6sR and IL-6 inhibited cell growth. Anti-IL6 neutralizing antibodies had no effect on PEL cell line proliferation; conversely, whereas anti-IL6R alone inhibited only weakly, anti-gp130 and anti-gp130 plus anti-IL6R showed strong inhibitory effects (>20% inhibition in 5/9 lines and >60% inhibition in 3/9 lines). In summary, PEL cell lines produce high amounts of cytokines (IL-6, IL-10, OSM); proliferation could be inhibited by blocking the receptors of the IL-6 signaling pathway.
Leukemia 1999 Apr
PMID:Constitutive cytokine production by primary effusion (body cavity-based) lymphoma-derived cell lines. 1021 73


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