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)

Lysis of target cells (TC) by cytolytic lymphocytes involves the secretion of cytoplasmic granules containing perforin and serine esterases by the effector cell (EC). Recently, a granule-independent cytolytic mechanism involving the interaction of the apoptosis-triggering Fas antigen (CD95) with Fas ligand (FasL) has been revealed in T cells. However, whether the Fas lytic pathway also functions in NK cells has not been established. We purified human peripheral NK cells (> 98% CD56+) and found that PMA and ionomycin treatment upregulated FasL message and stimulated the NK cells to lyse a Fas+ TC. This lysis was partially inhibited by the anti-Fas-blocking antibody M3 or by Fas.Fc fusion protein. We also found that FasL is constitutively expressed on the human NK-like leukemia cell line YT-INDY and that YT-INDY utilizes a Ca(2+)-independent Fas lytic pathway, as well as the granule pathway. We have previously shown that CD28/B7 interactions are involved in TC recognition by YT-INDY. K562 cotransfected with Fas and B7-1 (K562/Fas/B7) was lysed by YT-INDY at a higher level than a vector-transfected K562 line, whereas K562 transfected with Fas alone was not. Lysis of K562/Fas/B7 cotransfectants was partially Fas-mediated, as indicated by the presence of Ca(2+)-independent, M3-inhibitable lysis. Ca(2+)-independent, Fas-mediated lysis of several TC by YT-INDY was inhibited by anti-CD28 antibody. Anti-LFA-1 also inhibited Fas-mediated cytotoxicity in YT-INDY. Thus, fresh human NK cells and the human NK-like cell line YT-INDY are capable of using the Fas lytic pathway. In YT-INDY, CD28/B7 and LFA-1/ICAM interactions appear to influence the Fas lytic pathway.
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PMID:Fas involvement in cytotoxicity mediated by human NK cells. 749 25

Murine acquired immunodeficiency syndrome (MAIDS) is caused by a defective murine leukemia virus. The disease is characterized by abnormal lymphoproliferation, impaired T and B cell function and aberrant regulation of cytokines. Both T and B lymphocytes show activated phenotypes, but undergo apoptotic death with characteristic DNA fragmentation. These results indicate the presence of a continuous activation death pathway of the lymphocytes in MAIDS. Overexpression of the bcl-2 transgene in lymphocytes showed no effect on the apoptotic cell death or on the development of the disease. In contrast, mice carrying mutations in either Fas or Fas ligand exhibited accelerated progression of the disease upon infection with MAIDS virus. These results suggest the involvement of Fas-Fas ligand system in the pathogenesis of MAIDS.
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PMID:Apoptotic death of lymphocytes in murine acquired immunodeficiency syndrome: involvement of Fas-Fas ligand interaction. 758 5

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas-bearing cells. The membrane-bound human FasL was found to be converted to a soluble form (sFasL) by the action of a matrix metalloproteinase-like enzyme. Two neutralizing monoclonal anti-human FasL antibodies were identified, and an enzyme-linked immunosorbent assay (ELISA) for sFasL in human sera was established. Sera from healthy persons did not contain a detectable level of sFasL, whereas those from patients with large granular lymphocytic (LGL) leukemia and natural killer (NK) cell lymphoma did. These malignant cells constitutively expressed FasL, whereas peripheral NK cells from healthy persons expressed FasL only on activation. These results suggested that the systemic tissue damage seen in most patients with LGL leukemia and NK-type lymphoma is due to sFasL produced by these malignant cells. Neutralizing anti-FasL antibodies or matrix metalloproteinase inhibitors may be of use in modulating such tissue damage.
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PMID:Fas ligand in human serum. 861 31

Immune surveillance against tumors usually depends on T cell recognition of tumor antigens presented by major histocompatibility complex (MHC) molecules, whereas MHC class I- tumors may be controlled by natural killer (NK) cells. Perforin-dependent cytotoxicity is a major effector function of CD8+ MHC class I-restricted T cells and of NK cells. Here, we used perforin-deficient C57BL/6 (PKO) mice to study involvement of perforin and Fas ligand in tumor surveillance in vivo. We induced tumors in PKO and normal C57BL/6 mice by (a) injection of different syngeneic tumor cell lines of different tissue origin in naive and primed mice; (b) administration of the chemical carcinogens methylcholanthrene (MCA) or 12-O-tetradecanoylphorbol-13-acetate (TPA) plus 7,12-dimethylbenzanthracene (DMBA), or (c) by injection of acutely oncogenic Moloney sarcoma virus. The first set of models analyzes the defense against a tumor load given at once, whereas the last two sets give information on immune defense against tumors at the very moment of their generation. Most of the tumor cell lines tested were eliminated 10-100-fold better by C57BL/6 mice in an unprimed situation; after priming, the differences were more pronounced. Lymphoma cells transfected with Fas were controlled 10-fold better by PKO and C57BL/6 mice when compared to untransfected control cells, indicating some role for FasL in tumor control. MCA-induced tumors arose more rapidly and with a higher incidence in PKO mice compared to C57BL/6 or CD8-deficient mice. DMBA+TPA-induced skin papillomas arose with similar high incidence and comparable kinetics in both mouse strains. C57BL/6 and PKO mice have a similar incidence of Moloney murine sarcoma and leukemia virus-induced sarcomas, but tumors are larger and regression is retarded in PKO mice. Thus, perforin-dependent cytotoxicity is not only a crucial mechanism of both cytotoxic T lymphocyte- and NK-dependent resistance to injected tumor cell lines, but also operates during viral and chemical carcinogenesis in vivo. Experiments addressing the role of Fas-dependent cytotoxicity by studying resistance to tumor cell lines that were stably transfected with Fas neither provided evidence for a major role of Fas nor excluded a minor contribution of Fas in tumor surveillance.
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PMID:Decreased tumor surveillance in perforin-deficient mice. 892 Aug 66

We reported previously that CD4+ T cells and B cells in mice with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) caused by LP-BM5 murine leukemia virus (MuLV) mixtures increased the expression of Fas antigen (Fas) during progression of the disease. However, the contribution of the Fas/Fas ligand (Fas L) system to the pathogenesis of MAIDS remained unknown. Here, we examined the susceptibility of C57BL/6 (B6) lpr/lpr mice, which has been reported to be defective for the expression of Fas, to MAIDS. We found that the Thy1.2- CD4T cells and Ig kappa dull B220+ cells, which are characteristic of MAIDS, increased after the inoculation of LP-BM5 MuLV in B6 lpr/lpr mice. B220+ TCR alpha beta T cells, unique to lupus prone mice, also increased in the B6 lpr/lpr mice after infection. CD4+ B220+ TCR alpha beta T cells increased profoundly among the B220+ TCR alpha beta T cells from LP-BM5 MuLV-infected B6 lpr/lpr mice, while the B220+ TCR alpha beta T cells observed in non-infected B6 lpr/lpr mice were largely of the CD4-CD8- phenotype. A DNA PCR analysis of the LP-BM5 MuLV-infected B6 lpr/lpr mice revealed the genome integration of defective LP-BM5 virus, further confirming that MAIDS is inducible to B6 lpr/lpr mice. LP-BM5 MuLV-infected lpr/lpr mice died within 3 months, while MAIDS-infected B6 +/+ mice usually died within 5 to 6 months, and B6 lpr/lpr mice not infected with LP-BM5 MuLV lived more than 6 months. Taken together, these results suggest that MAIDS is inducible independently with functional Fas expression and the possibility of accelerated progression of murine AIDS and lpr-associated autoimmune disease in B6 lpr/lpr mice infected with LP-BM5 MuLV.
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PMID:Accelerated progression of a murine retrovirus-induced immunodeficiency syndrome in Fas mutant C57BL/6 lpr/lpr mice. 913 Feb 34

Binding of Fas ligand (FasL) or an agonistic anti-Fas receptor (Fas/CD95) antibody induces apoptosis in Fas-bearing target cells. The involvement of Fas/FasL pathway has been investigated in human acute myelogenous leukemia (AML) cells. Fas/CD95 is expressed on a majority of AML cells, although the intensity of expression is variable. The cross-linking with anti-Fas antibody can induce apoptotic cell death in certain cases of AML. When DNA synthesis and cell cycle progression are enhanced by growth-promoting cytokines, such as interleukin-3 and granulocyte-macrophage colony-stimulating factor, Fas-insensitive AML cells acquire cellular susceptibility toward Fas-mediated apoptosis. Cell cycle analysis reveals that Fas-mediated apoptotic signals can be transduced into cells in G1B compartment and G1A-->G1B transition might support the induction of Fas-mediated apoptosis. In addition, Fas-mediated apoptotic cell death of AML cells is also induced by interleukin-2-activated T cells expressing functional FasL on their surfaces. Activated T cells express a large amount of FasL mRNA, compared with freshly isolated T cells. The Fas/FasL pathway seems to be the major mechanism of T cell-mediated apoptosis in AML cells, although alternative mechanisms can also be operative. The induction of apoptosis in Fas/FasL system might be a novel and effective approach for leukemia immunotherapy.
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PMID:Fas receptor (CD95)-mediated apoptosis in leukemic cells. 913 Jun 10

The T-cell type of large granular lymphocyte (LGL) leukaemia is a lymphoproliferative disorder characterized by clonal proliferation of CD3+ LGL, which is often associated with autoimmune disorders. Phenotypic and functional data suggest that leukaemic CD3+ LGL represent activated cytotoxic T lymphocytes (CTL). One mechanism whereby CTL mediate target cell killing is through the Fas/Fas ligand apoptotic pathway. Fas ligand is expressed by CTL only after activation. In this study we examined seven patients with LGL leukaemia for expression of Fas ligand gene transcripts using reverse transcriptase-polymerase chain reaction (RT-PCR) analyses. We found constitutive expression of Fas ligand gene transcripts in each of the seven patients. Similar up-regulation of Fas ligand gene expression has been observed in mice with autoimmune lymphoproliferative syndromes caused by Fas mutations. However, sequence analyses of the death domain of the Fas gene in LGL leukaemia patients revealed no evidence for mutations. Our findings provide further support for the hypothesis that leukaemic LGL are CTL activated by chronic antigenic stimulation. Constitutive expression of Fas ligand may contribute to the pathogenesis of the neutropenia observed in LGL leukaemia.
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PMID:Constitutive expression of Fas ligand in large granular lymphocyte leukaemia. 913 51

Fas/APO-1 mediates apoptosis via Fas and Fas ligand transduction. Recently, a soluble form of Fas (sFas) was described which seems to be functionally implicated in the Fas signal system, suggesting a relationship between some disorders and sFas function. We measured sFas-levels in sera from normal controls and patients with disorders linked to human retroviral infection of human immunodeficiency virus (HIV) and human T-cell leukemia virus type-1 (HTLV-1). The sFas level of normal controls. HTLV-1 carriers seronegative for HIV, and patients with HTLV-1 associated myelopathy/tropical paraparesis (HAM/TSP), adult T-cell leukemia (ATL), and AIDS was 1.62 +/- 0.49, 1.90 +/- 0.49, 2.00 +/- 0.59, 3.32 +/- 2.05, and 3.06 +/- 0.92 ng/ml, respectively. Although the level of sFas in patient groups with HAM/TSP, ATL, and AIDS was significantly high in comparison to that of normal controls (p < 0.01), the individual values were highly variable within the groups. The sFas level was statistically correlated to the soluble interleukin-2 receptor (sIL-2R) level, as well as to cells expressing membrane Fas (mFas), indicating the same cellular origin. In some ATL cases, however, serum sFas levels and mFas expression density on leukemic T-cells were discrepant, with especially high levels of the soluble form and a lack of expression of the membrane form observed in 2 cases, sFas detection could serve as a putative marker for active diseases in patients with ATL and AIDS.
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PMID:Serum levels of soluble Fas/APO-1 receptor in human retroviral infection and associated diseases. 914 6

Fas ligand (FasL) plays a pivotal role in lymphocyte cytotoxicity and the maintenance of immunological homeostasis. Since FasL has been implicated in the existence of immunologically privileged body sites by inducing apoptosis of activated T lymphocytes, we investigated the expression of FasL in human colon cancers. We found that two out of seven primary tumors and all four hepatic metastatic tumors of surgically obtained colonic adenocarcinoma expressed FasL mRNA and protein, detected by reverse transcription-coupled PCR and by immunohistochemical staining, respectively. Expression of FasL was not detected in normal colonic epithelial cells. FasL mRNA was also expressed in some human colonic adenocarcinoma cell lines including SW480, SW1116, and LS180 cells. Cell-surface-associated FasL was detected in these human colon cancer cells by fluorescence immunocytochemical staining. In addition, the expressed FasL was demonstrated to be functional, since coculture experiments using FasL-expressing SW480 cells resulted in apoptosis of Jurkat T leukemia cells that are sensitive to Fas-mediated apoptosis, and this process was specifically inhibited by the neutralizing anti-human FasL antibody. Thus, our findings and other data suggest an alternative mechanism that enables tumors to evade immune destruction by inducing apoptosis in activated T lymphocytes. Furthermore, constitutive expression of FasL in hepatic metastatic tumors suggests that FasL may also be important in their colonization in the liver through induction of apoptosis in the surrounding Fas-expressing hepatocytes.
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PMID:Expression of Fas ligand in liver metastases of human colonic adenocarcinomas. 917 33

The Fas/Fas ligand (FasL) pathway is widely involved in apoptotic cell death in lymphoid and nonlymphoid cells. It has recently been postulated that many chemotherapeutic agents also induce cell death by activating the Fas/FasL pathway. In the present study we compared apoptotic pathways induced by anti-Fas or chemotherapeutic agents in the Jurkat human T-cell leukemia line. Immunoblotting showed that treatment of wild-type Jurkat cells with anti-Fas or the topoisomerase II-directed agent etoposide resulted in proteolytic cleavage of precursors for the cysteine-dependent aspartate-directed proteases caspase-3 and caspase-7 and degradation of the caspase substrates poly(ADP-ribose) polymerase (PARP) and lamin B1. Likewise, affinity labeling with N-(N(alpha)-benzyloxycarbonylglutamyl-N(epsilon)-biotinyllysyl+ ++)aspartic acid [(2,6-dimethyl-benzoyl)oxy]methyl ketone [Z-EK(bio)D-amok] labeled the same five active caspase species after each treatment, suggesting that the same downstream apoptotic pathways have been activated by anti-Fas and etoposide. Treatment with ZB4, an antibody that inhibits Fas-mediated cell death, failed to block etoposide-induced apoptosis, raising the possibility that etoposide does not initiate apoptosis through Fas/FasL interactions. To further explore the relationship between Fas- and chemotherapy-induced apoptosis, Fas-resistant Jurkat cells were treated with various chemotherapeutic agents. Multiple independently derived Fas-resistant Jurkat lines underwent apoptosis that was indistinguishable from that of the Fas-sensitive parental cells after treatment with etoposide, doxorubicin, topotecan, cisplatin, methotrexate, staurosporine, or gamma-irradiation. These results indicate that antineoplastic treatments induce apoptosis through a Fas-independent pathway even though Fas- and chemotherapy-induced pathways converge on common downstream apoptotic effector molecules.
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PMID:Comparison of apoptosis in wild-type and Fas-resistant cells: chemotherapy-induced apoptosis is not dependent on Fas/Fas ligand interactions. 924 21


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