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 Fas/Apo-1 receptor is an integral membrane protein that transduces apoptotic signals upon binding to its natural ligand or to specific antibodies. Loss of Fas/Apo-1 receptor leads in (lpr,lpr) mice to a nonmalignant accumulation of abnormal T-cells very probably due to the lack of induction of apoptosis in peripheral T-cells. It has been reported that soluble forms of Fas/Apo-1 receptor that may interfere with apoptotic signaling occur in patients suffering from various forms of lymphoid neoplasms. Therefore, we wished to investigate whether the loss of proper homeostatic regulation through Fas/Apo-1 receptor mediated apoptosis could influence the process of lymphomagenesis. To this end, we performed two experiments (i) we infected (lpr,lpr) animals with Moloney Murine Leukemia Virus (MoMuLV) that causes T-cell lymphoma in mice and (ii) we crossed (lpr,lpr) animals with E mu L-myc transgenic mice that are prone to develop T- and B-cell lymphoma due to deregulated expression of the L-myc transgene by the immunoglobulin enhancer E mu. We find that infection with MoMuLV did not accelerate the formation of lymphoid neoplasms in (lpr,lpr) mice when compared to infected normal animals. However, E mu L-myc/(lpr,lpr) animals that constitutively express the L-myc transgene in the lymphoid lineage clearly show accelerated formation of T- and B-cell lymphoma when compared to normal E mu L-myc transgenics. These data demonstrate that in cooperation with particular oncogenes impairment of Fas/Apo-1 receptor function can indeed affect and modulate the process of tumor formation.
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PMID:Loss of Fas/Apo-1 receptor accelerates lymphomagenesis in E mu L-MYC transgenic mice but not in animals infected with MoMuLV. 778 89

Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA-DR in class II+ T-cells, and that the homologous tyrosine kinase p72syk is stimulated in B-cells following ligation of class II antigens. Antibody mediated co-ligation of the T-cell antigen receptor (TCR/CD3) with class II molecules resulted in augmented tyrosine phosphorylation of ZAP-70. Comparable to antibody induced receptor ligation, bacterial superantigen (SEA and SEB) treatment of HLA-DR+ T-cells stimulated ZAP-70 tyrosine phosphorylation, consistent with class II transmembrane signaling by ligation of HLA-DR and V beta in cis. Modulation of the TCR/CD3 led to abrogation of class II induced ZAP-70 tyrosine phosphorylation, but did not result in sequestering of ZAP-70 from the cellular cytoplasm. Hyperphosphorylated ZAP-70 was associated with TCR/CD3 zeta-chain following cross-linking of HLA-DR, suggesting a mechanism for the TCR/CD3-dependence of class II induced signals in alloantigen-activated human T-cells. In both tonsillar B-lymphocytes and B-cell leukemia lines, p72syk was rapidly phosphorylated on tyrosine residues following HLA-DR cross-linking. Tyrosine phosphorylation of p72syk induced through ligation of either the B-cell antigen receptor or class II molecules was potently inhibited by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family of tyrosine kinases, leading functionally to a tyrosine kinase-dependent pathway of receptor-induced cell death.
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PMID:ZAP-70 and p72syk are signaling response elements through MHC class II molecules. 852 73

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

Cytotoxic drugs used in chemotherapy of leukemias and solid tumors cause apoptosis in target cells. In lymphoid cells the CD95 (APO-1/Fas)/CD95 ligand (CD95-L) system is a key regulator of apoptosis. Here we describe that doxorbicin induces apoptosis via the CD95/CD95-L system in human leukemia T-cell lines. Doxorubicin-induced apoptosis was completely blocked by inhibition of gene expression and protein synthesis. Also, doxorbicin strongly stimulates CD95-L messenger RNA expression in vitro at concentrations relevant for therapy in vivo. CEM and jurkat cells resistant to CD95-mediated apoptosis were also resistant to doxorbicin-induced apoptosis . Furthermore, doxorbicin-induced apoptosis was inhibited by blocking F(ab')2 anti-APO-1 (anti-CD95) antibody fragments. Expression of CD95-L mRNA and protein in vitro was also stimulated by other cytotoxic drugs such as methotrexate. The finding that apoptosis caused by anticancer drugs may be mediated via the CD95 system provides a new molecular insight into resistance and sensitivity toward chemotherapy in malignancies.
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PMID:Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. 861 18

In the study of apoptosis initiated by various signals including ligands binding to cell membrane receptors such as Fas and TNFRI, the sphingomyelin pathway and its resulting metabolites, the sphingolipids, have been suggested to be involved in the signaling pathway. In earlier studies we presented data which indicated that sphingosine (Sph) itself was increased during apoptosis induced by phorbol myristate acetate (PMA) in HL60 cells and tumor necrosis factor (TNF) in neutrophils, and when added exogenously was able to induce apoptosis. We report here that Sph and its methylated derivative N,N,-dimethylsphingosine (DMS) are able to induce apoptosis in cancer cells of both hematopoietic and carcinoma origin. In human leukemic cell lines CMK-7, HL60 and U937, treatment with 20 microM Sph for 6 hr caused apoptosis in up to 90% of cells. Human colonic carcinoma cells HT29, HRT18, MKN74 and COLO205 were shown to be more susceptible to apoptosis upon addition of DMS (>50%) than of Sph (<50%), yet were weakly or not sensitive to N,N,N-trimethylsphingosine (TMS). Under the same conditions, in the presence of serum, neither Sph-1-phosphate nor ceramide analogues C2-, C6- or C8-ceramide were able to induce apoptosis in any cell lines. However, in the absence of serum, ceramide analogues induced apoptosis in leukemia cell lines after 18 hr, yet much less so than Sph or DMS. Furthermore, apoptosis induced by Sph or DMS could not be inhibited by the ceramide synthase inhibitor fumonisin B1. Apoptosis was not induced by sphingolipids in primary culture cells, such as HUVEC or rat mesangial cells, but was apparent in transformed rat mesangial cells. Additionally, apoptosis induced by Sph, DMS or C2Cer was inhibited by protease inhibitors. Our data further support the evidence that the catabolic pathway of sphingomyelin involving Sph and other metabolites is an integral part of the apoptosis pathway.
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PMID:Sphingosine and its methylated derivative N,N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines. 862 Dec 58

Galectin-3 is a member (if a large family of beta-galactoside-binding animal lectins. It has been shown that the expression of galectin-3 is upregulated in proliferating cells, suggesting a possible role for this lectin in regulation of cell growth. Previously, we have shown that T cells infected with human T-cell leukemia virus type I express high levels of galectin-3, in contrast to uninfected cells, which do not express detectable amounts of this protein. In this study, we examined growth properties of human leukemia T cells transfected with galectin-3 cDNA, and thus constitutively overexpressing this lectin. Transfectants expressing galectin-3 displayed higher growth rates than control transfectants, which do not express this lectin. Furthermore, galectin-3 expression in these cells confers resistance to apoptosis induced by anti-Fas antibody and staurosporine. Galectin-3 was found to have significant sequence similarity with Bcl-2, a well-characterized suppressor of apoptosis. In particular, the lectin contains the NWGR motif that is highly conserved among members of the Bcl-2 family and shown to be critical for the apoptosis-suppressing activity. We further demonstrated that galectin-3 interacts with Bc1-2 in a lactose-inhibitable manner. We conclude that galectin-3 is a regulator of cell growth and apoptosis and it may function through a cell death inhibition pathway that involves Bcl-2.
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PMID:Expression of galectin-3 modulates T-cell growth and apoptosis. 869 88

Apoptosis plays a critical role during T cell development, both in the generation of functionally competent T cells in the thymus and the regulation of peripheral T cell populations. The fate of any T cell, whether it is developing in the thymus, or functioning in the peripheral immune system, is dependent on T cell receptor (TCR) specificity for antigens presented by MHC molecules and on the consequences of TCR-generated intracellular signalling pathways which lead to activation, anergy or apoptosis. This review describes data that have elucidated the way in which these highly regulated TCR-derived signalling pathways lead to such diverse final outcomes in thymocytes. Contributions to the induction of apoptosis in thymocytes by signalling pathways and receptors such as Fas, CD45 and CD28 are summarized, particularly with regard to the analysis of relevant transgenic mice. Developments concerning regulation of apoptosis by bcl-2 family members and the possible effectors of apoptosis, proteases, are assessed. Finally, this information is contrasted with the relatively scarce data on signalling pathways in thymic-derived T-ALL cells together with potential explanations of how transformation might occur by perturbation of apoptotic mechanisms. Precise understanding of these pathways may lead to the development of novel therapeutic reagents.
Leukemia 1996 Sep
PMID:The role of intracellular signalling pathways regulating thymocyte and leukemic T cell apoptosis. 875 58

Soluble receptors have been identified for most members of the TNF-receptor/NGF receptor superfamily. CD95 (Fas/Apo-1) is of particular importance, since its triggering may induce apoptosis in sensitive cells. Recently, a soluble form of the CD95 molecule was described which interacts with the CD95-CD95 ligand death pathway. Increased concentrations of soluble CD95 (sCD95) were previously detected in some patients with T and B cell leukemias and lymphomas. In the present study we investigated sCD95 in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. A total of 72 patients was studied (29 AML, 17 MDS, 20 CML and six other myeloproliferative disorders). In AML with active disease, the levels of sCD95 tended to be elevated, but did not correlate with defined clinical or laboratory parameters. In the other disorders, the levels of sCD95 were not generally increased, although some patients had elevated levels. These data strongly suggest that sCD95 in AML patients is not derived from leukemic cells, but is possibly secreted or shed from reactive or stromal cells. This hypothesis is also supported by a group of eight patients with septicemia but not leukemia who had elevated sCD95 (P < 0.05). Furthermore, all three patients with elevated sCD95 who had undergone chemotherapy for AML had major infections. Taken together, this study shows that measuring soluble Fas-receptor in myeloid leukemia is not diagnostically useful, but increased sCD95 may be associated with clinical complications like septicemias.
Leukemia 1996 Sep
PMID:Soluble FAS (CD95) is not elevated in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. 875 76

The Fas/Apo-1 molecule is a member of tumor necrosis factor/nerve growth factor (TNF/NGF) receptor family and is able to induce apoptosis in various type of malignant cells, including most of the human leukemia T-cells. We previously demonstrated that the Fas-resistant variants may exist in highly Fas-sensitive human leukemia T-cell lines. The surface expression of Fas antigen was unchanged in the variant cells, suggesting the requirement of the cytoplasmic mechanism to exert apoptosis. In the present study, we examined the changes in cytoplasmic proteins of the Fas-sensitive and Fas-resistant cells after stimulation with anti-Fas antibody, 2D1. In Western blotting analysis, we found that the stimulation of Fas-sensitive cells with 2D1, but not resistant variants, induced a repression of cyclin-dependent kinases (cdks), p34cdc2 and p33cdk2, along with apoptosis. There was no alteration in the expression of bcl-2, HSP70, HSP90, and cyclin proteins examined. This observation seemed specific to Fas-mediated apoptosis, because calcium ionophore A23187 or sodium azide failed to repress the expression of cdks. These results indicate that the specific depletion of cdks, most likely due to proteolysis, may play a role in Fas-mediated apoptosis.
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PMID:Selective depletion of cyclin-dependent kinases is associated with Fas-mediated apoptosis in human leukemia T-cell lines. 878 21

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


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