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 tax protein of human T-cell leukemia virus type I (HTLV-I) is known to be a potent transactivator of its own long terminal repeat (LTR) promoter and the cellular genes (IL-2, IL-2R, c-fos and GM-CSF). These effects of tax have been studied in vitro, mostly in T-cell lines. To determine its function in vivo in multiple cell types, we have used two transgenic mouse lines in which tax is expressed under the control of the LTR (LTRtax) or murine Thyl. 2 (Thytax) transcriptional regulatory sequences. Tax protein is expressed in fibroblasts, salivary gland, skeletal muscle, bone matrix and thymus tissue. In these tissues the expression of endogenous IL-2R, c-fos, GM-CSF, Zif268, IL-6, and PDGF-B were studied. In fibroblastic tumors GM-CSF, IL-6, PDGF-B, Zif268, c-fos were expressed at high levels. No significant changes in expression of these genes were seen in other tissues. This suggests that tax mediated transcriptional transactivation alone is not sufficient to cause accumulation of these cellular gene products. Other events which occur during tax mediated transformation in vivo allow high levels of cellular gene expression constitutively.
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PMID:[HTLV-I tax mediated activation of cellular genes in transgenic mice]. 191 30

Coordinate production of interleukin-1 beta (IL-1 beta) and granulocyte macrophage-colony stimulating factor (GM-CSF) or IL-6 by the blast cells of acute myeloblastic leukemia (AML) and normal peripheral blood leukocytes have been previously reported (van der Shoot et al.: Blood 74:2081-2087, 1989; Bradbury et al.: Leukemia 4:44-47 1990a, British Journal of Haematology 16:(in press), 1990b; Rodriguez-Cimadevilla et al.: Blood 76:1481-1489, 1990; Schindler et al.: Blood 75:40-47, 1990). In the present study, we show that IL-6 production by AML blasts is up-regulated by endogenously produced IL-1 beta. Neutralization of the endogenous source of IL-1 results in a significant decrease in IL-6 production, as determined by ELISA. Conversely, exposure of AML blasts to IL-1 alpha results in a significant increase in IL-6 production in 10 of 16 patient samples. Antibodies against IL-1 alpha and -beta also cause a drastic decrease in IL-6 and GM-CSF gene expression by the cells, suggesting that cytokine gene expression in AML blasts is driven, at least in part, by endogenous IL-1. The biologic significance of IL-6 production in culture of AML blasts has been addressed using a neutralizing antibody against IL-6. Our data indicate that IL-6 is important for the survival of clonogenic blasts in culture. In contrast, the survival of the total population of blasts is IL-6-independent, as assessed by the integrity of cellular DNA, even in the presence of anti-IL-6. These observations are consistent with the view that AML blasts might be organized as a lineage, with comparable hierarchy as in normal hemopoiesis and, perhaps, increased heterogeneity despite a homogenous appearance (McCulloch and Till: Blood Cells 7:63-77, 1981; Buick and McCulloch: Control of Animal Cell Proliferation. Academic Press, New York, vol. 1, pp. 25-57, 1985). Buick and McCulloch have identified a subpopulation of AML clonogenic cells with stem-cell-like properties, and suggested that the majority of blasts may have undergone a determination-like step. Our data indicate a marked difference in IL-6 requirement for cell survival between precursors and the majority of blasts, suggesting that IL-6 responsiveness may decrease following a determination-like event, i.e., the reduction in proliferative capacity.
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PMID:Interleukin-6 production by the blast cells of acute myeloblastic leukemia: regulation by endogenous interleukin-1 and biological implications. 191 69

After bone marrow transplantation many T-lymphocyte functions, including the production of cytokines (CK), such as interleukin 2, are severely depressed for months. The monocyte-derived cytokines tumor necrosis factor alpha and interleukin 6 are molecules central to immune functions. Moreover, they may be involved in graft-versus-host disease and in graft-versus-leukemia reaction. Hence, we have studied the reappearance of these CKs after BMT by analyzing whole blood cultures stimulated in vitro with lipopolysaccharide for 6 hr, followed by testing for the secretion of TNF in the WEHI 164/actinomycin D cytotoxicity bioassay and for IL-6 in the 7 TD 1 proliferation assay. We performed sequential studies in 6 children who were transplanted for aplastic anemia or leukemia with allogeneic bone marrow. We found that the production of both CKs can be induced as early as 10-14 days post BMT at the very beginning of engraftment, indicating that the regenerating monocyte system is recovering rapidly after BMT. Depletion and neutralization experiments confirmed that monocytes are the cellular source of the LPS-induced CK secretion after BMT. Control levels were reached 3 to 4 weeks post BMT. When analyzing the endotoxin-induced CK production in a larger panel of BMT patients after complete reconstitution, we could not detect any impact of acute or chronic GvHD, or of allogeneic or autologous BMT, nor did treatment with cyclosporine A (CsA) show any suppressive effect. Thus, our data show that the CK production of the monocyte/macrophage lineage is quite resistant to factors that do influence other cell lineages of the immune system during BMT. The coincident appearance of monocyte-derived cytokines and of GvHD suggests a role for these cytokines in GvHD in man.
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PMID:Recovery of monocytes after bone marrow transplantation--rapid reappearance of tumor necrosis factor alpha and interleukin 6 production. 192 48

Mometasone furoate (9 alpha, 21 dichloro-11 beta, 17 alpha dihydroxy-16 alpha methyl-1,4 pregnadiene-3, 20 dione-17-[2'] furoate) was an unexpectedly potent inhibitor of the in vitro production of three inflammatory cytokines, IL-1(1), IL-6, and TNF-alpha. The potency of mometasone furoate in inhibiting cytokine production was compared to that of hydrocortisone, betamethasone, dexamethasone, and beclomethasone. IL-6 and TNF-alpha were both produced by WEHI-265.1 (murine myelomonocytic leukemia) cells following stimulation by lipopolysaccharide (LPS). Twenty-four hours after stimulation by LPS, the cell-free supernatant fluids were removed. Their cytokine content was analyzed using ELISAs specific for each cytokine. IL-1 synthesis was induced in the harvested peritoneal macrophages of BALB/c mice by incubation with LPS for twenty-four hours. The IL-1 content in the cell-free supernatant fluids was determined by the thymocyte-costimulator bioassay. Using these systems, mometasone furoate was found to be the most potent steroid tested for inhibiting the production of the three cytokines. The IC50's were 0.05 nM (IL-1), 0.15 nM (IL-6), and 0.25 nM (TNF-alpha). The inhibition of the production of proinflammatory mediators by extremely low concentrations of mometasone furoate suggests that this steroid should be highly effective in various disorders.
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PMID:Cytokine inhibition by a novel steroid, mometasone furoate. 194 49

Evidence is presented that human monocytes and acute myeloblastic leukemic (AML) cells contain both high and low affinity binding sites for interleukin-4 (IL-4). On monocytes 183 +/- 132 high affinity binding sites per cell with a Kd of 60 +/- 29 pM and 1500 +/- 600 low affinity receptors with a Kd of 2.3 +/- 0.4 nM (X +/- S.D., n = 6) could be demonstrated. On AML cells (n = 11) a comparable number and binding affinity of IL-4 receptors were observed (77 +/- 36 high affinity receptors with Kd 72 +/- 31 pM and 2400 +/- 1000 low affinity receptors with Kd of 2.2 +/- 0.7 nM). In addition, no cross-competition was shown between radiolabeled IL-4 and IL-1-alpha, IL-3, IL-6, IL-7, G-CSF, and GM-CSF. Both types of receptors on monocytes as well as on leukemic blasts could be down-modulated in a similar fashion by IL-4 and activators of protein kinase C (PKC), but not by the calcium ionophore A23187. The down-modulation by PKC activators was caused by an increased internalization, degradation and release of radiolabeled IL-4 in the medium. Finally, the functionality of the IL-4 receptors were tested on AML cells with a 3H-thymidine proliferation assay. In 8/11 cases IL-4 affected AML proliferation. These data demonstrate two different binding sites for IL-4 on normal and leukemic cells, which can be modulated by external activation signals in an analogous way.
Leukemia 1991 Sep
PMID:Expression and regulation of IL-4 receptors on human monocytes and acute myeloblastic leukemic cells. 194 30

Previous studies have revealed a consistent defect in the cycling behavior of primitive neoplastic progenitor cells in patients with Philadelphia chromosome (Ph1)-positive chronic myeloid leukemia (CML). This is manifested both in vivo and in long-term cultures of CML cells as an increased rate of turnover amongst Ph1-positive progenitor cell types whose counterparts in normal individuals are mainly quiescent. To determine whether this deregulated proliferative activity of primitive Ph1-positive cells might be explained by a perturbation in the production of growth factors that regulate the turnover of primitive normal cells, the possibility of either autocrine or paracrine mechanisms of Ph1-positive cell stimulation was investigated. Northern blot analysis of total cellular RNA extracted from various CML blood cell populations showed no evidence of increased expression of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-3, IL-6, or tumor necrosis factor-alpha (TNF-alpha) compared with analogous normal peripheral blood cell populations in which transcripts for most of these growth factors are not detectable. A similar analysis of RNA extracted from the adherent layer of 4-week-old long-term cultures established from CML marrow (in which the Ph1-positive cells typically disappear) or from CML blood seeded onto normal marrow adherent layers (in which Ph1-positive cells typically persist) also revealed no difference in growth factor production compared with analogous cultures established with exclusively normal cells. For some of the growth factors studied, the assessment of bioactivity detectable in the medium confirmed the RNA data. There was also no evidence of a decreased production of putative inhibitors of primitive hematopoietic cells, i.e. transforming growth factor-beta and macrophage inflammatory protein-1 alpha by CML versus normal cells or cultures. These results do not support the existence of BCR-ABL induced autocrine or paracrine mechanisms in CML and suggest that constitutive activation of events normally dependent on growth factor receptor stimulation is more likely to underlie the lack of proliferation control exhibited by primitive Ph1-positive cells.
Leukemia 1991 Oct
PMID:Lack of evidence for abnormal autocrine or paracrine mechanisms underlying the uncontrolled proliferation of primitive chronic myeloid leukemia progenitor cells. 196 Oct 20

Tumor necrosis factor alpha (TNF-alpha) has been previously shown to modulate the expression of hematopoietic growth factor genes in monocytes and other mesenchymal cells. As acute myeloblastic leukemia (AML) blasts can express and produce hematopoietic growth factors, the influence of TNF-alpha on the accumulation of mRNAs for c-myc, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, IL-6 and IL-1 beta was evaluated in fresh blasts from 13 patients with AML. Total cellular RNA was extracted from blast cells cultured for 24 hours with or without TNF-alpha (500 U/ml). The c-myc transcript level was decreased by TNF-alpha treatment in 9/13 cases, and increased in only one case. Among the growth factor genes, the GM-CSF gene was more often and consistently influenced by TNF-alpha, increased levels of its transcript being observed in 6/13 cases following treatment with the cytokine; in no case was there a reduction of GM-CSF mRNA. G-CSF and IL-6 transcripts were more heterogeneously influenced, whereas the IL-3 transcript was never detected in our AML samples. The IL-1 beta message was present in 8/13 untreated and in 13/13 TNF-alpha treated samples. Moreover, in untreated cells, GM-CSF, G-CSF and IL-6 expression was always associated with IL-beta expression. These findings indicate that TNF-alpha can modulate the levels of growth factor transcripts in AML blasts, and raise questions about the effects of TNF-alpha on leukemic hematopoiesis, considering that TNF-alpha, IL-1 and GM-CSF can synergistically stimulate the growth of AML clonogenic cells.
Leukemia 1991 Oct
PMID:Tumor necrosis factor alpha modulates the messenger RNA expression of hematopoietic growth factor genes in fresh blast cells from patients with acute myeloblastic leukemia. 196 Oct 22

CMK is a human cell line derived from a megakaryoblastic leukaemia. It has characteristics of the megakaryocytic lineage, such as the presence of platelet peroxidase, membrane glycoproteins (GP)Ib and GPIIb/IIIa, alpha-granules, and demarcation membranes. The cell line proliferates autonomously in serum-containing medium. Here we report that the cell line expresses the gene for IL-6 and releases small quantities of the cytokine into the medium. Addition of exogenous IL-6 to cultures seeded into medium was found to promote growth of the cells. Conversely, addition of a neutralizing anti-IL-6 antibody inhibited cell growth. These data support the notion that autocrine IL-6 is one of the factors accounting for autonomous growth of the cell line.
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PMID:Interleukin 6, a possible autocrine growth and differentiation factor for the human megakaryocytic cell line, CMK. 199 94

Alteration and abnormal expression of the c-myc oncogene were investigated in human multiple myeloma. Human myeloma cells were highly purified (more than 95%) from bone marrow aspirates in 14 cases of advanced multiple myelomas and one case of plasma cell leukaemia. Southern blotting revealed that a rearranged configuration of c-myc gene was found in only one case of them, but this was a novel truncation of the gene in its coding exon II; a rearranged 3.4 kb band was detected by digestion with Xba I using c-myc exon II probe, but no rearranged band was found using exon III probe. In this case, the truncated c-myc allele was not transcribed; normal sized (2.4 kb) c-myc mRNA was markedly expressed, but no aberrant mRNA was detected. On the other hand, by Northern blotting, the nine cases, including the case with the rearranged c-myc gene, showed increased expression of normal sized (2.4 kb) c-myc mRNA. Elevated c-myc mRNA expressions were well related to the in vitro proliferation (3H-TdR uptake), but not to IL-6 response. Interestingly, extremely high expressions of c-myc mRNA were detected in two cases of aggressive myelomas, including the case with the rearranged c-myc gene, and in one of plasma cell leukaemia. These two cases of aggressive myelomas were the ones who showed the markedly high 3H-TdR uptakes, and had the common clinical features with the formation of an extramedullary mass and very short survival. These results suggest that the activation of c-myc gene could induce high proliferative activities and the subsequent aggressive transformation of myeloma cells.
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PMID:Increased expression of the c-myc gene may be related to the aggressive transformation of human myeloma cells. 202 78

A human plasma cell leukaemia cell line (HSM-2) and a subclone (HSM-2.3) have been established from the bone marrow of a patient with bi-phenotypic leukaemia. Proliferation assays using a variety of cytokines demonstrated that HSM-2 proliferated in response to recombinant interleukin-6 (rIL-6), but did not respond to rIL-1, rIL-2, rIL-3, rIL-4, rIL-5, recombinant granulocyte-colony stimulating factor (rG-CSF), or recombinant granulocyte-macrophage-colony stimulating factor (rGM-CSF), and that HSM-2.3 responded to rIL-3 and rIL-6. HSM-2 expressed the CD38 (OKT10), PCA-1, cytoplasmic-IgM, and surface kappa light chain. HSM-2.3 expressed the CD14 (My4), CD33 (My9), CD38 (OKT10), CD19 (B4), CD24 (OKB2), CD10 (J5), PCA-1. HSM-2 and HSM-2.3 are useful tools for analysing the possible role of IL-3 and IL-6 in the oncogenesis of plasma cell leukaemia.
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PMID:Establishment and characterization of a plasma cell leukaemia cell line dependent for growth on IL-6 and a bi-phenotypic subclone dependent upon both IL-3 and IL-6. 206 60


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