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)

TEL (Translocation-ETS-Leukemia or ETV 6) is disrupted by multiple chromosomal translocations in acute leukemia. The loss of heterozygosity at the TEL locus in leukemias and the hemizygous deletion of TEL that is observed in various tumors, suggests that TEL is a tumor suppressor. Overexpression of TEL alters cellular morphology and represses the expression of the matrix metalloproteinase stromelysin-1. Based on these studies, deletion analysis was used to define the minimal repression domains of TEL. TEL-mediated repression required both the N-terminal pointed domain and a central region composed of amino acids 268-303. The mSin3A and N-CoR corepressors bind to the pointed domain and the central repression domain of TEL, respectively. Unexpectedly, histone deacetylase-3, but not other histone deacetylases, also associates with the central region of TEL. Histone deacetylase-3 interacts with a TEL mutant that cannot bind N-CoR, suggesting that this is a direct interaction with TEL. In addition, histone H3 was under-acetylated near the TEL-binding sites in the endogenous stromelysin-1 promoter when TEL was expressed. Furthermore, trichostatin A, a potent histone deacetylase inhibitor, impaired TEL-dependent repression of the stromelysin-1 promoter. Finally, while TEL-expression induced cellular aggregation of Ras-transformed cells, Trichostatin A reversed the TEL-induced cellular aggregation phenotype. Thus, the cumulative data suggests that histone deacetylase-3 activity is required for the transcriptional functions of TEL.
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PMID:TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. 1143 34

Plasma from a total of 57 patients with adult T-cell leukaemia (ATL) (acute ATL, 39 patients; lymphoma ATL, one patient; chronic ATL, 15 patients; smouldering ATL, two patients) and 20 healthy controls was analysed for the presence of type IV gelatinase activity with clinical features. A significant elevation of plasma matrix metalloproteinase-9 (MMP-9) was observed in some ATL patients, particularly in the patients with malignant cell infiltration. MMP-9 was found to be secreted into the conditioned medium from all ATL cell lines examined. Moreover, the corresponding mRNA was detectable both in all ATL cell lines examined and in the majority of primary acute ATL cells, indicating that ATL cells are capable of synthesizing and secreting MMP-9. We previously demonstrated that a high incidence of ATL cell infiltration was closely related to a high plasma level of vascular endothelial growth factor (VEGF) produced by ATL cells themselves. This present study showed that the presence of increased plasma MMP-9 was closely associated with elevated plasma VEGF in ATL patients. Furthermore, we showed that both increased plasma MMP-9 and VEGF were significantly related to high ATL cell infiltration. All these findings strongly suggest that MMP-9 and VEGF act co-operatively in the process of ATL cell invasion.
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PMID:Matrix metalloproteinase-9 and vascular endothelial growth factor: a possible link in adult T-cell leukaemia cell invasion. 1184 1

Besides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMPs) play critical roles in angiogenesis, tumor invasion and metastasis. Increased angiogenesis is observed in chronic B lymphocytic leukemia (B-CLL) and published data reported VEGF and bFGF production in this disease. The purpose of this study was to investigate MMP expression in early stage B-CLL. Elevated MMP-9 concentrations were detected by ELISA in the sera of B-CLL patients (median level 250 ng/ml) compared with healthy donors (67 ng/ml) (P < 0.0001), and immunostaining with antibodies against MMP-9 and B cell antigens (CD19, CD23) substantiated the presence of MMP-9 in tumoral B lymphocytes. By using RT-PCR, ELISA and zymography experiments, we confirmed that B-CLL cells expressed and released the pro-form of MMP-9 with Mr 92 kDa (158-1300 pg/ml/10(6) cells/48 h), p-aminophenylmercuric acetate generating a 82 kDa active form. In contrast, the production of MMP-9 by normal counterpart B cells was significantly low (28-169 pg/ml/10(6)cells/48 h). Moreover, B-CLL culture supernatants contained bFGF (median levels 17 pg/ml/10(6) cells/48 h), VEGF (1.4 pg/ml/10(6) cells/48 h) and TNF-alpha (0.2 pg/ml/10(6) cells/48 h). TNF-alpha and VEGF antibodies blocked MMP-9 at the mRNA and protein levels. Interferons (IFNs) type I or type II repressed MMP-9 gelatinolytic activity in a dose and time dependency, and this was reflected by a parallel inhibition of MMP-9 mRNA and protein. IFNs however did not affect the production of bFGF, VEGF and TNF-alpha. Together, our data show that B-CLL lymphocytes synthesize MMP-9 and emphasize the specific inhibitory actions of IFNs on its expression.
Leukemia 2002 May
PMID:Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons. 1198 39

Butyric acid (BA) induces differentiation of human leukemia, including HL-60 cells. By using a fluorescent probe, we showed that reactive oxygen species (ROS) were generated in BA-treated cells. BA-induced differentiation was accompanied with an increased secretion of pro-matrix metalloproteinase (MMP)-9. Both phenomena were inhibited by antioxidants. Tissue inhibitors of MMP (TIMP)-1 and -2 secretion were increased by BA, but differently affected by antioxidants. By contrast, BA did not affect MMP-9 mRNA, and decreased TIMP-1 and TIMP-2 mRNA levels. In addition, migratory and invasive properties of HL-60 cells were enhanced by BA, but differently affected by antioxidants. Altogether, these results indicate that ROS are messengers of BA-induced differentiation and increased invasiveness.
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PMID:Butyric acid increases invasiveness of HL-60 leukemia cells: role of reactive oxygen species. 1199 38

To further elucidate the role of angiogenesis in the pathogenesis of chronic myelogenous leukemia (CML) we evaluated the effects of the bcr-abl translocation on the secretion of the angiogenic factors VEGF, FGF-2, HGF, IL-8 and matrix metalloproteinases (MMPs) as well as on the angiogenic potential in vivo of bcr-abl+ cells. First, we examined murine FL5.12 cells transfected with the bcr-abl constructs p185, p210 and p230 and found that the transfected cells secreted as much as four-fold more VEGF (p185 > p210 >p230) than wild-type (wt) cells, as well as MMP-9 and MMP-2. When Matrigel fragments containing these bcr-abl+ cells were implanted subcutaneously in SCID or Balb-C mice they became significantly more vascularized and hemoglobinized than implants containing normal or wt cells (p185 > p210 > p230). Similarly, we found that myeloblasts expanded from bone marrow (BM) CD34+ cells derived from Philadelphia-positive CML patients secreted up to 10 times more VEGF, FGF-2, HGF and IL-8 compared to myeloblasts derived from normal donors' BM CD34+ cells and that BM mononuclear cells (MNC) isolated from CML patients induced vascularization of Matrigel implants in mice. Moreover, we found that peripheral blood MNC expressed MMP-2 and membrane-type (MT)1-MMP in about 50% of CML patients studied, and MMP-9 in all of them. Furthermore, VEGF stimulated the secretion of MMP-9 in these primary CML cells. We conclude that stimulation of angiogenesis by angiogenic factors, including MMPs, could play an important role in the pathogenesis of CML, suggesting that therapies targeting the newly formed endothelium could be developed for CML.
Leukemia 2002 Jun
PMID:Bcr-abl-positive cells secrete angiogenic factors including matrix metalloproteinases and stimulate angiogenesis in vivo in Matrigel implants. 1204 Apr 48

Aclarubicin (ACLA), which belongs to the anthracycline class of antineoplastic agents, has been demonstrated as a differentiating agent of human leukemia, including HL-60 cells. We report here on the incidence of ACLA-induced differentiation on matrix metalloproteinase (MMP) expression and cell invasiveness. The aim of this study was to investigate the involvement of reactive oxygen species (ROS) as mediators of ACLA-induced effects. By using a fluorescent probe, we showed that subtoxic (i.e. differentiating) concentration of ACLA generate reactive oxygen species in HL-60 cells. ACLA-differentiated cells exhibited an increased proMMP-9 secretion which has been observed by gelatin zymography and immunoassay. Antioxidants were able to inhibit ACLA-induced differentiation and proMMP-9 secretion. Furthermore, RT-PCR showed that ACLA increased MMP-9 and tissue inhibitor of MMP (TIMP-1) expression in a ROS-dependent manner. In addition, the migration and invasion capacities of HL-60 cells were enhanced by ACLA treatment, but only partially reversed by antioxidants. Altogether, these results evidenced ROS as messengers of ACLA-induced differentiation and MMP-9 expression.
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PMID:Involvement of reactive oxygen species in aclarubicin-induced differentiation and invasiveness of HL-60 leukemia cells. 1211 37

Among the 25 bis(cyclopentadienyl)vanadium(IV) and 14 oxovanadium(IV) compounds synthesised and evaluated for anticancer activity, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (metvan) was identified as the most promising multitargeted anticancer vanadium complex with apoptosis-inducing activity. At nanomolar and low micromolar concentrations, metvan induces apoptosis in human leukaemia cells, multiple myeloma cells and solid tumour cells derived from breast cancer, glioblastoma, ovarian, prostate and testicular cancer patients. It is highly effective against cisplatin-resistant ovarian cancer and testicular cancer cell lines. Metvan is much more effective than the standard chemotherapeutic agents dexamethasone and vincristine in inducing apoptosis in primary leukaemia cells from patients with acute lymphoblastic leukaemia, acute myeloid leukaemia or chronic acute myeloid leukaemia. Metvan-induced apoptosis is associated with a loss of mitochondrial transmembrane potential, the generation of reactive oxygen species and depletion of glutathione. Treatment of leukaemia cells from acute lymphoblastic leukaemia, acute myeloid leukaemia and chronic acute myeloid leukaemia patients with metvan inhibits the constitutive expression as well as the gelatinolytic activities of matrix metalloproteinase-9 and -2. Treatment of human malignant glioblastoma and breast cancer cells with metvan at concentrations > 1 microM is associated with a nearly complete loss of the adhesive, migratory and invasive properties of the treated cancer cell populations. Metvan shows favourable pharmacokinetics in mice and does not cause acute or subacute toxicity at the dose levels tested (12.5 - 50 mg/kg). Therapeutic plasma concentrations > or = 5 microM, which are highly cytotoxic against human cancer cells, can be rapidly achieved and maintained in mice for at least 24 h after intraperitoneal bolus injection of a single 10 mg/kg non-toxic dose of metvan. Metvan exhibits significant antitumour activity, delays tumour progression and prolongs survival time in severe combined immunodeficient mouse xenograft models of human malignant glioblastoma and breast cancer. The broad spectrum anticancer activity of metvan together with favourable pharmacodynamic features and lack of toxicity warrants further development of this oxovanadium compound as a new anticancer agent. Metvan could represent the first vanadium complex as an alternative to platinum-based chemotherapy.
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PMID:Metvan: a novel oxovanadium(IV) complex with broad spectrum anticancer activity. 1245 42

The process of implantation and trophoblast invasion is currently considered as the most limiting factor for the establishment of pregnancy. Molecular interactions at the embryo-maternal interface during the time of adhesion and subsequent invasion are crucial to the process of embryonic implantation. Both partners, the mother as well as the embryo, play equal roles in the embryo-maternal dialogue, the embryonic part being the main topic in this study. Investigations of the proteins in the extra-embryonic matrices (i.e. zona pellucida) indicate that the embryo participates intensively in this early embryo-maternal signalling. One unique feature during implantation process of primate embryos is the release of chorionic gonadotrophin, which seems to influence endometrial activity by two different mechanisms: (i) luteotrophic activity with increasing progesterone release and (ii) a direct action on the endometrium. Furthermore, embryonic interleukin-1beta may be involved in embryo-maternal signalling. Other significant signals in this interaction are most likely leukaemia inhibitory factor (LIF) and colony-stimulating factor (CSF), which stimulate matrix metalloproteinase (MMP)/insulin-like growth factor binding protein-1 (IGFBP-1) activity and the insulin-like growth factor (IGF) system, which is modulated by embryonic IGFBP-3. Similar significances are discussed for uteroglobin and haptoglobin. Finally, the phenomenon of maternal immunological tolerance, triggered by the presence of the early embryo, is fundamental to the understanding of implantation and trophoblast invasion. A tightly regulated balance between activated and inactivated T cells at the implantation site may control the beginning of adequate trophoblast invasion and also limit this invasion to a tolerable extent for the maternal system, consequently ensuring a biologically healthy haemo-chorial placenta.
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PMID:Embryo-maternal signalling: how the embryo starts talking to its mother to accomplish implantation. 1267 10

Fusogenic membrane glycoproteins (FMG) are potent therapeutic transgenes with potential utility in the gene therapy of gliomas. FMG expression constructs caused massive syncytia formation followed by cytotoxic cell death in glioma cell lines, and antitumor activity has been shown in glioma xenografts. FMG-induced fusion in glioma cells can involve heterologous cell lines including normal astrocytes and fibroblasts, therefore making targeting important. Here we report on the use of matrix metalloproteinase (MMP) cleavable linkers to target cytotoxicity of FMGs against gliomas. Expression constructs were made expressing the hyperfusogenic version of the Gibbon Ape Leukemia Virus envelope glycoprotein (GALV) linked to a blocking ligand (the C-terminal extracellular domain of CD40 ligand) via either an MMP cleavable linker (GALV M40), a factor Xa protease cleavable linker (GALV X40), or a noncleavable linker (GALV N40). Unmodified GALV expressing constructs were used as positive controls. The glioma cell lines U87, U118, and U251 previously characterized by zymography and MMP-2 activity assay as high, medium, and low MMP expressors, respectively; normal human astrocytes and the MMP-poor cell line TE671 were transfected with the GALV, GALV N40, GALV X40, and GALV M40 constructs. In contrast to unmodified GALV constructs, transfection with GALV X40 and GALV N40 constructs blocked fusion and cytotoxic cell death. Fusion occurred, however, after transfection with constructs containing MMP cleavable linkers to an extent dependent on MMP expression in the specific cell line. Use of the broad-spectrum MMP inhibitors, 1,10-phenanthroline and N-hydroxy-piperazine-carboxamide completely abolished the ability of MMP constructs to induce fusion. In cell mixing experiments, mixing of MMP-poor cell lines transfected with GALV M40 constructs with the MMP overexpressing untransfected U87 glioma cells led to partial restoration of fusion. Use of U87 supernatant did result in a similar effect. Establishment of stable tranfectants expressing the membrane-type MMPs, MT-1 MMP and MT-2 MMP did restore fusion in the MMP-poor cell line TE671 after transfection with GALV M40, thus indicating that both membrane-type MMPs and soluble MMPs activate the MMP cleavable constructs. In addition, the GALV M40 construct retained its cytotoxic activity against U87 cells in vivo, although less effectively as compared to unmodified GALV. Our data indicate that GALV-induced cytotoxicity in glioma cell lines can be blocked by display of the CD40 ligand. Incorporation of an MMP cleavable linker can selectively restore cytotoxicity in MMP expressing glioma cell lines both in vitro and in vivo, while sparing normal human astrocytes. Given the high frequency of MMP overexpression in gliomas, this represents a promising targeting strategy.
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PMID:Targeting the cytotoxicity of fusogenic membrane glycoproteins in gliomas through protease-substrate interaction. 1270 11

Overexpression of urokinase-type plasminogen activator receptor (uPAR) on tumor cell surface is essential for invasion and metastasis in a variety of tumor cells. To establish a retroviral-mediated antisense RNA transfer system of uPAR gene for exploring its function on down-regulation of uPAR expression in leukemia cells, the retroviral vector LaCD87SN was constructed by inserting uPAR gene into LXSN vector in an antisense orientation. An uPAR gene antisense RNA transfer system was established by liposome-mediated transfection in combination with cross infection with retrovirus. Human leukemia cells U937 were transduced with aCD87 amphotropic retrovirus, expressing uPAR antisense RNA, and the U937/aCD87 cells was obtained by G418 selection. The integration and expression of antisense uPAR gene were analyzed by polymerase chain reaction (PCR) assay. The cell surface expression of CD87 and the activities of matrix metalloproteinase (MMP) were assayed by flow cytometry (FCM) and gelatin zymography, respectively. The results showed that the amphotropic retroviral producers Am12/aCD87, which expressed antisense RNA of uPAR gene with a titer of 6.3 x 10(5) cfu/ml in supernatants, were obtained by means of transfection and superinfection. U937/aCD87 cells were established by continuative G418 selection after retrovirus infection. In U937/aCD87 cells, the integrated provirus and the overexpression of antisense uPAR gene was confirmed. Compared with U937/NeoR cells, FCM analysis revealed that CD87 expression on U937/aCD87 cell surface was not downregulated significantly. However, MMP-9 secretion was significantly suppressed in U937/aCD87 cells. In conclusion, although the retroviral-mediated antisense RNA transfer could not efficiently suppress uPAR expression on leukemic cell surface, it may interfere the uPAR-MMP interactions.
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PMID:[Establishment of urokinase receptor gene antisense RNA transfer system and its application in leukemia research]. 1470 41


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