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 cytokines interleukin (IL)-6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitor factor (LIF), oncostatin M (OSM) and probably the recently cloned cytokine cardiotrophin-1, signal, in combination with their specific receptors, through the common signal transducer gp130. Here, we report that the signaling activities of IL-6, IL-11, CNTF and OSM/LIF can be specifically blocked by different anti-gp130 monoclonal antibodies (mAb). Furthermore, we found two mAb, B-P8 and B-S12, which directly activate gp130 independently of the presence of cytokines or their receptors. This agonistic activity includes induction of cytokine-dependent cell proliferation and stimulation of acute-phase protein synthesis in liver cells. Compared to B-P8 mAb, the B-S12 mAb exhibited the strongest agonistic activity, while both mAb are synergistic in their action. This activity could not be blocked by inhibiting mAb against IL-6 and the IL-6 receptor. In contrast to F(ab')2 of B-S12 which still could activate gp130, Fab fragments completely lost their agonistic activity. Activation by tyrosine phosphorylation of the transcription factors Stat1 and APRF/Stat3 was also induced by B-S12 and B-P8, suggesting that both mAb induce homodimerization of gp130. Since hematopoietic stem cells express gp130 on their plasma membrane, it was anticipated that the agonistic anti-gp130 mAb could stimulate the proliferation of these stem cells. Indeed, B-S12 and B-P8 were able to stimulate CD34+ cells. In summary, our data show for the first time that mAb against gp130 can specifically block the action of distinct IL-6-type cytokines that signal through gp130. Such mAb might be of great value for therapeutic applications in diseases where a single cytokine action needs to be inhibited. In addition, the agonistic gp130 mAb may be used as growth factors for maintenance and expansion of stem cells prior to grafting.
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PMID:Interleukin-6 signal transducer gp130 has specific binding sites for different cytokines as determined by antagonistic and agonistic anti-gp130 monoclonal antibodies. 856 40

The novel hematopoietic growth factor FLT3 ligand (FL) is the cognate ligand for the FLT3, tyrosine kinase receptor (R), also referred to as FLK-2 and STK-1. The FLT3R belongs to a family of receptor tyrosine kinases involved in hematopoiesis that also includes KIT, the receptor for SCF (stem cell factor), and FMS. the receptor for M-CSF (macrophage colony- stimulating factor). Restricted FLT3R expression was seen on human and murine hematopoietic progenitor cells. In functional assays recombinant FL stimulated the proliferation and colony formation of human hematopoietic progenitor cells, i.e. CD34+ cord and peripheral blood, bone marrow and fetal liver cells. Synergy was reported for co-stimulation with G-CSF (granulocyte-CSF). GM-CSF (granulocyte-macrophage CSF), M-CSF, interleukin-3 (IL-3), PIXY-321 (an IL-3/GM-CSF fusion protein) and SCF. In the mouse, FL potently enhanced growth of various types of progenitor/precursor cells in synergy with G-CSF, GM-CSF, M-CSF, IL-3, IL-6, IL-7, IL-11, IL-12 and SCF. The well-documented involvement of this ligand-receptor pair in physiological hematopoiesis brought forth the question whether FLT3R and FL might also have a role in the pathobiology of leukemia. At the mRNA level FLT3R was expressed by most (80-100%) cases of AML (acute myeloid leukemia) throughout the different morphological subtypes (MO-M7), of ALL(acute lymphoblastic leukemia) of the immunological subtypes T-ALL and BCP-ALL (B cell precursor ALL including pre-pre B-ALL, cALL and pre B-ALL), of AMLL (acute mixed-lineage leukemia), and of CML (chronic myeloid leukemia) in lymphoid or mixed blast crisis. Analysis of cell surface expression of FLT3R by flow cytometry confirmed these observations for AML (66% positivity when the data from all studies are combined), BCP-ALL (64%) and CML lymphoid blast crisis (86%) whereas less than 30% of T-ALL were FLT3R+. The myeloid, monocytic and pre B cell type categories also contained the highest proportions of FLT3R+ leukemia cell lines . In contrast to the selective expression of the receptor, FL expression was detected in 90-100% of the various cell types of leukemia cell lines from all hematopoietic cell lineages. The potential of FL to induce proliferation of leukemia cells in vitro was also examined in primary and continuously cultured leukemia cells. The data on FL-stimulated leukemia cell growth underline the extensive heterogeneity of primary AML and ALL samples in terms of cytokine-inducible DNA synthesis that has been seen with other effective cytokines. While the majority of T-ALL (0-33% of the cases responded proliferatively; mean 11%) and BCP-ALL (0-30%; mean 20%) failed to proliferate in the presence of FL despite strong expression of surface FLT3R, FL caused a proliferative response in a significantly higher percentage of AML cases (22-90%; mean 53%). In the panel of leukemia cell lines examined only myeloid and monocytic growth factor- dependent cell lines increased their proliferation upon incubation with FL, whereas all growth factor-independent cell lines were refractory to stimulation. Combinations of FL with G-CSF, GM-CSF, M-CSF, IL-3, PIXY- 321 or SCF and FL with IL-3 or IL-7 had synergistic or additive mitogenic effects on primary AML and ALL cells, respectively. The potent stimulation of the myelomonocytic cell lines was further augmented by addition of bFGF (basic fibroblast growth factor), GM-CSF, IL-3 or SCF. The inhibitory effects of TGF-beta 1 (transforming growth factor-beta 1) on FL- supported proliferation were abrogated by bFGF. Taken together, these results demonstrate the expression of functional FLT3R capable of mediating FL- dependent mitogenic signaling in a subset of AML and ALL cases further underline the heterogeneity of AML and ALL samples in their proliferative response to cytokine.
Leukemia 1996 Apr
PMID:Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. 861 33

Thrombopoietin (TPO) is a recently characterized growth and differentiation factor for megakaryocytes and platelets exerting its effects via the receptor MPL. We examined the expression of MPR on the cell surface of a panel of 43 myelomonocytic, erythroid and megakaryocytic leukemia cell lines and 21 primary acute myeloid leukemia (AML) cases by flow cytometry. With few exceptions MPL was found on all 32 erythroid/megakaryocytic cell lines and on all 11 growth factor-dependent myelomonocytic cell lines, albeit at variable percentages and intensities per cell population (with a 10% cut-off level for positivity still 30/43 cell lines scored as MPL positive). The majority of the primary AML samples (including all seven M6/M7 cases) expressed the MPL protein regardless of the morphological and immunological subtype (13/21 cases had >10% MPL-positive cells). Recombinant TPO overexpressed in hamster cells induced a mitogenic response in seven cell lines (one growth factor-independent and six factor-dependent lines) and in 3/21 AML specimens (two AML M2, one AML M7) as measured by 3H-thymidine incorporation. Expression of MPL clearly did not correlate with response to TPO. For further detailed studies of the interaction of TPO with other cytokines we used the AML M7-derived M-07e cells as an informative indicator cell line for which both murine and human TPO acted as a very potent mitogen in a dose-dependent fashion (3- to 11-fold proliferation increase relative to medium alone). This growth factor-dependent cell line which is normally cultured in conditioned medium containing several cytokines could be grown in long-term culture supplemented only with TPO. Co-incubation of M-07e with various cytokines and TPO showed additive proliferative effects for interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and synergistic responses for stem cell factor (SCF), interferon (IFN)-alpha, and to a lesser extent for IFN-gamma and tumor necrosis factor (TNF)-alpha. Erythropoietin (EPO), IL-1, IL-6, IL-11 and leukemia inhibitory factor (LIF), know as megakaryocytic maturation-inducing molecules, were not substantially effective, neither singly nor in combination with TPO, with regard to cell growth. Transforming growth factor (TGF)-beta1 antagonized the inductive effect of TPO on M-07e cell growth. Addition of TPO to cultures of megakaryocytic cell lines failed to significantly alter the ploidy distribution and the differentiation marker immunoprofile of the cells indicating a lack of maturation-inducing effects in this model system. In summary, TPO represents an efficient in vitro potentiator of megakaryocytic leukemia proliferation of at least some primary cases or cell lines. While TPO seems to be the major physiological regulator of megakaryocytopoiesis, the present data suggest also some proliferative effects on certain leukemia cells, apparently on non-megakaryocytic leukemia cells as well, thus assigning to TPO a possible pathobiological role in leukemogenesis which would be of clinical relevance. Our data show that the response to TPO is not restricted to cells committed to the megakaryocytic differentiation pathway as we could demonstrate TPO-responsive megakaryocytic and non-megakaryocytic cell lines; thus, these cell lines represent powerful tools in such analyses. Consequently, this new cytokine needs to be properly examined so we can get a clear understanding of the clinical possibilities and dangers.
Leukemia 1996 Feb
PMID:Expression of the receptor MPL and proliferative effects of its ligand thrombopoietin on human leukemia cells. 863 39

A consensus regarding myeloma cell growth factor responsiveness and ability to produce autocrine interleukin (IL)-6 has not yet been obtained. In this study, we have established three new human myeloma cell lines (DP-6, KAS-6/1 and KP-6) from patients with aggressive disease. Extensive characterization of these cell lines revealed considerable heterogeneity at several levels. Growth factor responsiveness was initially addressed. Although the potent myeloma cell growth factor, IL-6, induced the proliferation and allowed for the expansion of all three cell lines, a panel of other cytokines elicited heterogeneous responses in each cell line. IL-3, IL-10, IL-11, insulin-like growth factor-I and tumor necrosis factor-alpha also stimulated DNA synthesis in all three cell lines; however, the magnitude of the response was generally lower than that observed in cultures containing IL-6. Transforming growth factor-beta, by contrast, uniformly inhibited the growth of all three cell lines. IL-1alpha and IL-1beta induced the proliferation of the DP-6 cells, but had minimal effects on the KAS-6/1 and KP-6 cells. Interferon (IFN)-alpha stimulated DNA synthesis in the KAS-6/1 cells, but inhibited the proliferation of the DP-6 and KP-6 cells. By comparison, IFN-gamma induced the growth of the KAS-6/1 and DP-6 cells, but inhibited the KP-6 cells. The gp130-associated cytokines, IL-11, leukemia inhibitory factor and oncostatin M, stimulated the growth of the KAS-6/1 cells, but had minimal effects on the DP-6 and KP-6 cells. The cell lines were also analyzed for IL-6 expression. RT-PCR analysis demonstrated that all three cell lines expressed IL-6 mRNA. However, when culture supernatants were tested using a sensitive IL-6 ELISA or IL-6 bioassay only the DP-6 and KP-6 cells were shown to be secreting biologically active IL-6. In summary, although all three of these cell lines were established from myeloma patients, the heterogeneity observed between these cell lines was considerable and may reflect, as well as provide tools to study, the heterogeneity observed in clinical disease.
Leukemia 1996 May
PMID:Establishment and characterization of three myeloma cell lines that demonstrate variable cytokine responses and abilities to produce autocrine interleukin-6. 865 85

The expression of transcripts of cytokines of the interleukin-6 (IL-6) family has been examined in human breast tumors, breast cancer cell lines, and adipose stromal cells, by means of reverse transcription polymerase chain reaction amplification. Of the six breast tumor samples examined, all expressed transcripts encoding IL-6 and Leukemia Inhibitory Factor (LIF). Four of the samples also expressed transcripts for oncostatin M (OSM) and IL-11, and three expressed the IL-6 receptor. Adipose stromal cells expressed IL-6, IL-11 and LIF, but not the IL-6 receptor, consistent with previous conclusions that IL-6 activity in these cells required addition of IL-6 soluble receptor. In the case of T47D cells, expression of IL-11 protein was confirmed by immunotitration. Moreover, in these cells, expression of IL-11 transcripts was induced 3-fold by addition of estradiol to the culture medium. These results add credence to our previous proposal that breast cancer development is regulated in part by local autocrine and paracrine mechanisms via epithelial/mesenchymal interactions, in which estrogen produced by stromal cells surrounding the tumor acts to stimulate the production of growth factors and cytokines by the tumor cells. Some of these may act to stimulate further the growth and development of the tumor, while these or other factors may act on the surrounding mesenchymal cells in a paracrine fashion to stimulate aromatase expression in the presence of glucocorticoids. Thus, a positive feedback loop is established which leads to the development and growth of the tumor.
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PMID:Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells. 873 8

The present review has summarized the expression, production and effects of the human interleukins (IL) 1-11 and myelopoietic colony stimulating factors (CSF) in the established myeloid leukemia cell lines and in cells from patients with acute myeloid leukemia as well as the oncogene expression reported in these myeloid leukemia cell lines. The genetic dissection of leukemic myelopoiesis may provide new perspectives for the control of myeloid leukemias. Based on their expression of phenotypic markers (e.g., surface antigens, cytochemical staining, etc.), myeloid cell lines can be further subdivided into myelogenous, monocytic, erythroid and megakaryoblastic leukemia cell lines. Due to the close relationship of erythroid and megakaryoblastic progenitor cells and to the existence of a probably common precursor cell giving rise to these two different cell lineages, many megakaryoblastic cell lines express erythroid markers (e.g., expression of hemoglobin or glycophorin A) and conversely cell lines with a predominant erythroid profile might display megakaryoblastic features (e.g., platelets peroxidase or glycoproteins CD41, CD42b or CD61). The recent cloning of the specific cytokine: thrombopoietin (TPO) and its receptor generated a strong interest in these particular myeloid cell lines that are discussed in more detail in the present review. Both normal and leukemic megakaryocytopoiesis are stimulated by granulocyte-macrophage colony stimulating factor (GM-CSF), IL-3, GM-CSF/IL-3 fusion protein, IL-6, IL-11 and TPO but inhibited by IL-4, interferon-alpha (IFN-alpha) and IFN-gamma. Human megakaryoblastic leukemia cell lines have common biological features: high expression of the megakaryocytic specific antigen (CD41); high expression of early myeloid antigens (CD34, CD33 and CD13); constitutive expression of IL-6 and platelet-derived growth factor; a complex karyotype picture; expression of c-kit (the stem cell factor receptor); growth-dependency or -stimulation by IL-3 and/or GM-CSF; and in vivo tumorigenicity in mice associated with marked fibrosis. Whereas numerous chemical and biologic agents induce granulocytic and/or monocytic differentiation of myeloid leukemia cell lines, only a few agents including phorbol myristate acetate, vitamin D3, IFN-alpha, IL-6 and thrombin have been reported to induce megakaryocytic differentiation in the megakaryoblastic leukemia cells.
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PMID:Interleukins and colony stimulating factors in human myeloid leukemia cell lines. 875 Jun 18

The serial change of various cytokines in the serum from a patient with cyclic thrombocytopenia is described. Interleukin 7, stem cell factor, and transforming growth factor beta 1 synchronized with the platelet count, and there was a significant positive correlation between the three cytokines and the platelet count. Levels of macrophage colony-stimulating factor, thrombopoietin, platelet-associated IgG and erythropoietin changed reciprocally with the platelet count, and there was a significant negative correlation between the platelet count and these cytokines except erythropoietin. No cyclic change was observed in IL-3, IL-6, IL-11, granulocyte-macrophage colony-stimulating factor, or leukaemia inhibitory factor. These observations suggest that this disease involves two cyclic changes: megakaryocytopoiesis and platelet destruction, in both of which the cytokines play an important role.
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PMID:Cyclic change of cytokines in a patient with cyclic thrombocytopenia. 875 31

Toxohormones are tumor-derived factors that induce cancer cachexia syndrome in tumor-bearing animals. Nude mice bearing tumors induced by eight human cancer cell lines with this activity were studied for cytokine production and expression of a newly identified gene, ob, which has the ability to control body weight. A melanoma cell line, SEKI, and a neuroepithelioma cell line, NAGAI, produced a large amount of the cytokine, leukemia-inhibitory factor (LIF). A uterine carcinoma cell line, Yumoto, produced a large amount of interleukin 6 (IL-6), and an oral cavity carcinoma cell line, OCC-1C, concomitantly produced LIF, IL-6, and IL-11. Reverse transcription polymerase chain reaction studies revealed that ob gene mRNA was not expressed in any of these cell lines, suggesting that the gene does not have a role as a tumor product responsible for cancer cachexia in this model. These findings suggest that in four of eight animal models in which cancer cachexia syndrome developed, LIF, IL-6, or possibly IL-11 produced by cancer cells may be toxohormones, but in the remaining four cancer cell lines the mechanism responsible for cachexia syndrome remains unknown.
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PMID:Toxohormones responsible for cancer cachexia syndrome in nude mice bearing human cancer cell lines. 876 17

A novel human leukaemic cell line, designated CTS, was established from the peripheral blood of a 13-year-old girl suffering from acute myeloblastic leukaemia (AML) in relapse. CTS cells expressed CD7, CD13, CD33, CD34 and HLA-DR antigens, and showed ultrastructural myeloperoxidase activity. In addition, CTS cells showed DNA rearrangements of the immunoglobulin heavy chain gene and the light kappa chain gene, and deletions of the T-cell receptor delta 1 gene. Cytogenetic analysis revealed a human female diploid karyotype with a t(6;11)(q27;q23) chromosomal translocation. Molecular studies demonstrated a DNA rearrangement of the MLL gene, the expression of a truncated 11.0 kb MLL mRNA and the detection of the MLL/AF-6 fusion transcript in CTS cells. To our knowledge, this cell line is the first report of a human leukaemic cell line with a t(6;11) chromosomal translocation. CTS cells showed no significant proliferative response to the cytokines, IL-2, IL-3, IL-6, IL-11, GM-CSF, G-CSF, EPO, SCF, but were induced to differentiate to the T-cell, B-cell, erythroid or megakaryocytic lineage in the presence of particular cytokines. This CTS cell line may provide a useful tool in the study of the oncogenesis of mixed lineage leukaemia with 11q23 abnormalities and for the analysis of growth and differentiation of pluripotent stem cells.
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PMID:A novel human leukaemic cell line, CTS, has a t(6;11) chromosomal translocation and characteristics of pluripotent stem cells. 890 86

We have a previously reported that interleukin-10 (IL-10) is a potent but IL-6-unrelated growth factor for freshly explanted myeloma cells (Lu et al, Blood 85:2521, 1995). We have also shown that exogenous IL-10 supported the growth of XG-1 and XG-2 human myeloma cell lines (HMCL) through an IL-6-independent mechanism. (Lu et al, Blood 85:2521, 1995). Because the IL-10 receptor does not involve the gp 130 IL-6 transducer, we have attempted to elucidate the mechanisms of IL-10 action on myeloma cells. Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines. We found that myeloma cells from XG-1 and XG-2 HMCL and from 5 of 6 patients' tumoral samples produced oncostatin M (OM) constitutively but failed to produce IL-6, IL-11 and leukemia-inhibitory factor (LIF). The autocrine OM was inactive in the absence of IL-10 due to lack of a functional OM receptor on myeloma cells. IL-10, by inducing the receptor for LIF (LIFR), produced a functional autocrine OM loop in XG-1 and XG-2 cells and in primary myeloma cells from 2 patients. We also found that some myeloma cell lines (XG-4, XG-6, and XG-7) an fresh myeloma cells from 3 of 6 patients produced an autocrine IL-10 and that these cells constitutively expressed LIFR. One HMCL (XG-7) produced IL-10, OM, and IL-6 an expressed LIFR. The XG-7 cells used OM and IL-6 as autocrine growth factors. We have previously shown that IL-10 could induce IL-11 receptor in myeloma cells and confer on them sensitivity to IL-11 (Lu et al, FEBS Lett 377:515, 1995). Taken together, these results show that IL-10 is a key cytokine for inducing the expression of LIFR and IL-11R and possibly another uncharacterized OM coreceptor on myeloma cells and that OM and IL-10 might be produced by myeloma cells. They also emphasize that all myeloma cell growth factors reported to data involve an activation of the gp130 IL-6 transducer.
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PMID:Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop. 891 64


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