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

Research in cytokine biology has grown exponentially in recent years as cytokines (often also termed growth factors) are now known to be involved in a wide range of pathological and physiological processes. Continuous human leukemia cell lines represent powerful tools to investigate these mechanisms. Most cell lines grow autonomously in standard culture media (containing fetal bovine serum) independent of externally added growth stimuli. Over the last 5-10 years a battery of myeloid leukemia-derived cell lines has been established that is constitutively dependent on the addition of cytokines to the culture. Such factor-dependent cell lines die rapidly by apoptosis when deprived of the appropriate growth factor. We determined the cytokine response profiles of 19 absolutely growth factor-dependent leukemia cell lines with myelomonocytic, erythroid or megakaryocytic phenotypes with regard to enhanced or suppressed cellular proliferation. Cells were incubated in liquid culture with optimal concentrations of various recombinant human cytokines known to have effects on the growth of hematopoietic cells. A proliferative or anti-proliferative response to these 41 cytokines was assessed by the short-term 3H-thymidine uptake assay. A proliferative response was considered as positive when the stimulation index (SI) was >2; inhibition was regarded as significant with an SI <0.5. The response profile of each cell line to these 41 cytokines was different and individual. None of the cell lines responded to one or two factors only (minimum to at least five cytokines). Proliferation of most (n = 13-17), but not of all cell lines was significantly enhanced by GM-CSF, IL-3, PIXY-321, SCF and IFN-gamma. TGF-beta1 consistently inhibited proliferation (in 11/19 cell lines). IFN-alpha, IFN-beta, TNF-alpha and TNF-beta had either stimulatory or inhibitory effects. The cell lines responding most often proliferatively (to 15-19 different cytokines) were UCSD/AML1, HU-3, TF-1 and M-07e. In summary, these factor-responsive human leukemia cell lines represent extremely useful model systems for the analysis of cytokine effects on hematopoietic cells. The cytokine response profiles of the individual cell lines provide guidelines for the selection of the appropriate cell culture for such experiments.
Leukemia 1997 May
PMID:Cytokine response profiles of human myeloid factor-dependent leukemia cell lines. 918 Feb 95

We have examined the in situ transcription of leukaemia inhibitory factor (LIF) in brain tissue from 3 cases of subacute sclerosing panencephalitis (SSPE) and in 2 non-neurological control brains. This has been compared with expression of interleukin 2 (IL-2), interleukin 6 (IL-6) and tumour necrosis factor beta (TNF beta) in the same tissues. All of the cytokines in the study were expressed in cells in the inflammatory infiltrate as well as in glial cells. LIF mRNA was also found to be expressed in neurons, in foci where these cells were also virally infected. No hybridization was found with any of the probes in areas of SSPE brain, which were negative for measles virus RNA or in the non-neurological control cases, although expression was demonstrated in the latter by use of reverse transcription-polymerase chain reaction (RT-PCR). Differentiated, cultured human neuronal cells were also positive, by RT-PCR, for LIF. This is the first demonstration of LIF expression in human brain and the results suggest that this cytokine is up-regulated, in several cell types, including neurons, following virus infection.
 ...
PMID:Leukaemia inhibitory factor mRNA is expressed in the brains of patients with subacute sclerosing panencephalitis. 920 69

We previously have exposed U-937 human leukemia cells to stepwise increased concentrations of the anticancer drug etoposide, and this treatment has resulted in stable sublines (termed U-937/RE) exhibiting various extents of resistance to the drug and constitutively expressing c-fms mRNA, a specific marker of monocytic differentiation. In this report, we pursued studies to show that the P-glycoprotein blocker, verapamil, partially restores sensitivity to etoposide in U-937/RE cells. Further, the U-937/RE cells exhibit differential sensitivities to compounds that induce maturation of U-937 cells, as judged by the ability to reduce nitroblue tetrazolium and by morphologic changes, and increased sensitivities to apoptosis induction by the cytokines tumor necrosis factor (TNF) and lymphotoxin (LT) and the anticancer drugs 9-nitrocamptothecin and doxorubicin. In addition, the U-937/RE cells, xenografted in immunodeficient mice, demonstrate decreased or no ability to induce tumors. Taken together, these findings indicate that U-937/RE cells differ from the parental U-937 cells in several functional properties and can serve as models to develop protocols for treatment of human leukemia.
 ...
PMID:Altered sensitivities to anticancer and differentiation agents in etoposide-resistant human myeloid leukemia U-937 cells. 950 84

Lymphotoxin-alpha (LT), also called TNF-beta, which belongs to the 'TNF family' was originally isolated from a lymphoblastoid cell line. LT enhances the proliferation of activated B cells and augments B cell proliferation induced by IL-2. It functions as an autocrine growth factor for EBV-infected B cell lines and has been implicated in the pathogenesis of B cell malignancies. We tested the expression of LT mRNA in B-CLL and found that LT was expressed in highly purified leukemic cells in 11 out of 11 patients examined. Regulation of expression of LT mRNA is aberrant in B-CLL cells, since LT mRNA expression was not detected in fresh peripheral blood mononuclear cells or B cells identified in seven out of seven normal individuals. In addition, LT mRNA expression was detected for up to 6 days in purified unstimulated in vitro cultures of B-CLL cells. Glucocorticosteroids, that have been effectively used in the treatment of lymphoid malignancies, were added to the cultures and abrogated the LT mRNA expression after an incubation time of 12 h. Addition of recombinant LT to cultures increased proliferation of B-CLL cells while proliferation of these cells was inhibited by antisense oligonucleotides against LT mRNA. B-CLL cells cultured with LT antisense oligonucleotides (asLT) as well as glucocorticoid-treated cells showed reduced viability and a DNA fragmentation ladder characteristic of apoptosis suggesting a relationship between down-regulation of LT mRNA expression and the induction of apoptosis. These studies support the role of LT in the growth regulation and development of B-CLL cells.
Leukemia 1998 Apr
PMID:Lymphotoxin-alpha is an autocrine growth factor for chronic lymphocytic leukemia B cells. 955 6

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.
 ...
PMID:Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). 976 76

A novel biphenotypic leukemia cell line, NALM-29, was established from a 46-year-old Japanese male patient with acute lymphoblastic leukemia (ALL). The primary leukemic blasts showed a common ALL phenotype with CD19+, CD10+, CD13-, HLA-DR+ and Igs-. NALM-29 cells display biphenotypic characteristics: expression of the intracellular enzyme myeloperoxidase at the mRNA and protein level and cell surface positivity for CD19, CD10, CD13, CD33 and HLA-DR. NALM-29 fulfills EGIL criteria as B-cell precursor (BCP) leukemia B-II type. NALM-29 cells have a lymphoblastic morphological appearance; the immunoglobulin heavy chain gene is rearranged. NALM-29 cells responded significantly to the proliferative stimuli of FLT-3 ligand and IL-7, but not to GM-CSF, IL-3, IL-6, PIXY-321 or SCF. Proliferation of cells was inhibited significantly by IL-4, TNF-alpha or TNF-beta treatment. Cytogenetic analysis revealed the characteristic t(9;22)(q34;q11); expression of the m-bcr e1-a2 BCR-ABL fusion gene (typically found in ALL) was determined by PCR amplification of cDNA. The immunological, cytogenetic and functional characterization of NALM-29 suggests that this cell line may represent a scientifically significant in vitro model for BCP-type leukemia cells with biphenotypic characteristics.
 ...
PMID:A novel biphenotypic B-cell precursor leukemia cell line (NALM-29) carrying t(9;22)(q34;q11) established from a patient with acute leukemia. 1045 71

Natural killer cells mediate spontaneously secretory/necrotic killing against rare leukemia cell lines and a nonsecretory/apoptotic killing against a large variety of tumor cell lines. The molecules involved in nonsecretory/apoptotic killing are largely undefined. In the present study, freshly isolated, nonactivated, human NK cells were shown to express TNF, lymphotoxin (LT)-alpha, LT-beta, Fas ligand (L), CD27L, CD30L, OX40L, 4-1BBL, and TNF-related apoptosis-inducing ligand (TRAIL), but not CD40L or nerve growth factor. Complementary receptors were demonstrated to be expressed on the cell surface of solid tumor cell lines susceptible to apoptotic killing mediated by NK cells. Individually applied, antagonists of TNF, LT-alpha1beta2, or FasL fully inhibited NK cell-mediated apoptotic killing of tumor cells. On the other hand, recombinant TNF, LT-alpha1beta2, or FasL applied individually or as pairs were not cytotoxic. In contrast, a mixture of the three ligands mediated significant apoptosis in tumor cells. These findings demonstrate that human NK cells constitutively express several of the TNF family ligands and induce apoptosis in tumor cells by simultaneous engagement of at least three of these cytotoxic molecules.
 ...
PMID:Constitutive expression and role of the TNF family ligands in apoptotic killing of tumor cells by human NK cells. 1055 60

OX40 is a member of the tumor necrosis factor (TNF) receptor superfamily and known to be an important costimulatory molecule expressed on activated T cells. To investigate the role of costimulation of OX40 in human immunodeficiency virus type 1 (HIV-1) infection by its natural ligand, gp34, the OX40-transfected ACH-2 cell line, ACH-2/OX40, chronically infected with HIV-1, was cocultured with paraformaldehyde (PFA)-fixed gp34-transfected mouse cell line, SV-T2/gp34. The results showed that HIV-1 production was strongly induced. This was followed by apparent apoptosis, and both processes were specifically inhibited by the gp34-specific neutralizing monoclonal antibody 5A8. Endogenous TNF alpha (TNF-alpha) and TNF-beta production were not involved in the enhanced HIV-1 production. Furthermore, enhanced HIV-1 transcription in gp34-stimulated ACH-2/OX40 cells was dependent on the kappa B site of the HIV-1 long terminal repeat, and the OX40-gp34 interaction activated NF-kappa B consisting of p50 and p65 subunits. When primary activated CD4(+) T cells acutely infected with HIV-1(NL4-3) (CXCR4-using T-cell-line-tropic) were cocultured with PFA-fixed gp34(+) human T-cell leukemia virus type 1-bearing MT-2 cells or SV-T2/gp34 cells, HIV-1 production was also markedly enhanced. The enhancement was again significantly inhibited by 5A8. The present study first shows that OX40-gp34 interaction stimulates HIV-1 expression and suggests that OX40 triggering by gp34 may play an important role in enhancing HIV-1 production in both acutely and latently infected CD4(+) T cells in vivo.
 ...
PMID:OX40 stimulation by gp34/OX40 ligand enhances productive human immunodeficiency virus type 1 infection. 1143 53

An autoimmune mechanism in the pathogenesis of myelodysplastic syndrome (MDS) is suggested by response to immunosuppression, with CD8+ T-lymphocytes implicated in the haematopoietic suppression. We therefore sought evidence for human leucocyte antigen (HLA) restriction and variant frequency differences in selected polymorphisms at the loci for the immunomodulatory cytokines, tumour necrosis factor alpha (TNF-alpha), lymphotoxin-alpha (LT-alpha) and interleukin 10 (IL-10) in patients with MDS and acute myeloid leukaemia (AML) compared with normal controls. DNA from 150 MDS/AML patients [24 AML, 53 refractory anaemia (RA), 25 RA with excess blasts (RAEB), four RAEB in transformation (RAEBt), 21 sideroblastic leukaemia, 22 chronic myelomonocytic leukaemia] was screened. Control data was from Scottish blood donors (HLA class I/II), healthy General Practitioner-based subjects (TNF-alpha/LT-alpha) and published values (IL-10). HLA class I/II haplotypes were determined using sequence-specific primers. Polymorphisms were assayed at TNF-alpha -308, LT-alpha +252 and IL10 -824, -597 and -1082 loci. Variant frequencies of common haplotypes at HLA class I and II, high-/low-producer TNF-alpha/LT-alpha and IL-10 loci were not different between patients and controls or within the French-American-British, International Prognostic Scoring System or cytogenetic subgroups and were not associated with altered survival for MDS/AML patients. TNF2 allele frequency was greater in the MDS/AML cohort (chi2 = 6.593, P < 0.05) but the biological significance was uncertain in the absence of an increased high-producer TNF-alpha/LT-alpha haplotype frequency. We can find no genetic influence for these polymorphisms in HLA class I/II, TNF-alpha/LT-alpha and IL-10 loci on either predisposition or disease progression in MDS/AML.
 ...
PMID:Allele and haplotype frequency at human leucocyte antigen class I/II and immunomodulatory cytokine loci in patients with myelodysplasia and acute myeloid leukaemia: in search of an autoimmune aetiology. 1202 20

Human T-cell leukemia virus type I (HTLV-I) provirus load differs more than 100-fold among carriers and a high provirus load in the peripheral blood mononuclear cells (PBMCs) is regarded as a risk factor for both preleukemic states and inflammatory diseases including HTLV-I-associated myelopathy (HAM). We examined polymorphisms in the genes for tumor necrosis factor (TNF), TNF receptor type 1 and 2, lymphotoxin (LT)-alpha, interleukin (IL)-1beta, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and mannose binding protein (ManBP) in 143 HTLV-I carriers whether these polymorphisms affect the provirus load in the PBMCs of carriers. No significant association was observed between these polymorphisms and the provirus load. Homozygotes for a ManBP-variant allele, however, showed a tendency for the decreased number of provirus load. When combined, the data on the alleles of LT-alpha and MCP-1, HTLV-I carriers having high producer alleles of both genes showed a trend for increased provirus load. These data suggest that inflammation or an active immune response may induce an increased amount of HTLV-I-infected T cells, leading to a high provirus load.
 ...
PMID:Influence of cytokine and mannose binding protein gene polymorphisms on human T-cell leukemia virus type I (hTLV-I) provirus load in HTLV-I asymptomatic carriers. 1265 Oct 71


<< Previous 1 2 3 4 5 6 7 Next >>