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)

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

The monoclonal antibody anti-APO-1 induces apoptosis upon triggering the cell surface molecule APO-1 (CD95), a novel member of the tumor necrosis factor/nerve growth factor receptor superfamily. We tested the efficacy of APO-1 mediated apoptosis in a model system of human leukemia in SCID mice. T-ALL cells recovered from SCID mice were sensitive towards anti-APO-1 mediated apoptosis when tested in vitro. In vivo, treatment of leukemia-bearing SCID mice with anti-APO-1 induced programmed cell death in a substantial fraction of T-ALL cells, thus leading to significantly prolonged survival. Anti-APO-1 treatment, however, failed to completely eliminate all leukemic cells. This may be due to resistance towards anti-APO-1 mediated apoptosis in a fraction of T-ALL cells. Thus, identification of cellular programs which determine sensitivity and resistance towards apoptosis may provide new perspectives for rational therapeutic interventions.
Leukemia 1994 Nov
PMID:APO-1 (CD95) mediated apoptosis in human T-ALL engrafted in SCID mice. 752 86

Murine monoclonal antibody (mAb) 7C11 binds to the same cell surface epitope as anti-APO-1 and anti-Fas and reacts specifically with cells transfected with a cDNA encoding the human Fas antigen. Furthermore, incubation with 7C11 causes death of hematopoietic cell lines that express APO-1/Fas but not APO-1/Fas-negative cell lines. 7C11 therefore recognizes the human APO-1/Fas (CD95) antigen, a 40 to 50 kDa cell surface glycoprotein that can trigger apoptosis or programmed cell death. Expression of APO-1/Fas antigen by normal and neoplastic hematopoietic cells was determined by flow cytometry using 7C11. APO-1/Fas is expressed by approximately 30 to 40% of resting peripheral blood T cells, B cells, and monocytes and by approximately 5% of resting NK cells and thymocytes. It was not detected on granulocytes, erythrocytes, or platelets. Approximately 80 to 90% of activated T cells, B cells, and thymocytes express APO-1/Fas, as do the majority of activated NK cells. Perturbation of APO-1/Fas by 7C11 does not affect the viability of resting lymphocytes or monocytes. In contrast, activated T cells and NK cells undergo apoptosis within 3 hours of exposure to 7C11. Other mAb that stimulate T cells or NK cells do not cause rapid induction of programmed cell death. APO-1/Fas antigen is expressed by many cell lines of lymphoid and myeloid lineage. However, this antigen was detected on neoplastic cells from only one of 69 patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, or multiple myeloma. Only 3 out of 25 tumor samples from patients with non-Hodgkin's lymphoma were found to express APO-1/Fas. All three of these lymphomas harbored the bcl-2-Ig fusion gene associated with the chromosomal translocation t (14;18). Conversely, only 27% of lymphomas that possessed the bcl-2-Ig gene were found to express the APO-1/Fas antigen. Like normal activated lymphocytes, leukemia and lymphoma cells that expressed APO-1/Fas antigen were found to undergo apoptosis in vitro after incubation with 7C11. The APO-1/Fas antigen appears to regulate the growth of normal hematopoietic cells, and the marked upregulation of this antigen on activated normal lymphocytes contrasts sharply with the absence of APO-1/Fas on neoplastic cells of hematopoietic lineage. Defects in the apoptotic signal delivered through this antigen might contribute to the pathogenesis of hematopoietic neoplasms. Thus, the gene encoding APO-1/Fas can be considered a novel type of tumor suppressor gene, just as bcl-2 can be considered a cellular proto-oncogene.
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PMID:Functional consequences of APO-1/Fas (CD95) antigen expression by normal and neoplastic hematopoietic cells. 753 60

Cell line NKL was established from the the peripheral blood of a patient with CD3-CD16+CD56+ large granular lymphocyte (LGL) leukemia. The neoplastic LGL of this patient mediated natural killing and antibody-dependent cellular cytotoxicity (ADCC) and exhibited proliferative responses similar to normal CD16+CD56dim natural killer (NK) cells. The Morphology of NKL cells resembles that of normal activated NK cells. The karyotype of NKL is 47, XY, add (1) (q42), +6 del (6) (q15 q23), del (17) (p11). NKL cells express CD2, CD6, CD11a, CD26, CD27, CD29, CD38, CD43, CD58, CD81, CD94, CD95, class II MHC, and the C1.7.1 antigen, but do not express detectable levels of CD3, CD4, CD5, CD8, CD14, CD19, CD20, CD28, alpha/beta or gamma/delta T cell receptors on the cell surface. The density of the CD16, CD56, and CD57 antigens declined markedly on NKL cells during prolonged im vitro culture. Nevertheless, NKL cells can mediate ADCC as well as natural killing. NKL cells are strictly dependent on interleukin-2 (IL-2) for sustained growth and die if deprived of IL-2 for more than 7 days. NKL cells proliferate in response to concentrations of IL-2 as low as 1 pM, but an optimal proliferative response requires approximately 100 pM IL-2. NKL cells growing in the presence of IL-2 express abundant IL-2R alpha with little or no detectable IL-2 beta or gamma chain on the cell surface; NKL cells deprived of IL-2 express high levels of both IL-2R alpha and beta. IL-4, IL-7, and IL-12, unlike IL-2, do not maintain the viability of NKL cells. Furthermore, IL-1, IL-4, IL-6, IL-7, IL-12, tumor necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha) and IFN-gamma do not support the growth of NKL cells. The NKL cell line may prove useful for studies of human NK cell biology.
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PMID:Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia. 859 69

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

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

Large granular lymphocyte leukemia (LGLL) is defined as clonal proliferation of LGLs in peripheral blood. The following studies were conducted to address some issues in chronic LGLL. (1) Chronic LGLL is characterized by the indolent course, and the diagnosis of leukemia is difficult in such patients as those without distinct organomegaly and/or any evidence of monoclonality. We performed immunohistological studies in a patient with persistent NK lymphocytosis. No organomegaly had been seen in the patient during a three-year-observation, who died from cerebrovascular accident. The autopsy findings revealed multi-organ infiltration including spleen, liver, bone marrow, lymph nodes and lung. These findings suggest that the cells of chronic LGLL have infiltrative capacity characteristic of malignant cells. (2) Lymphocytosis in chronic LGLL is usually stable for a long period. We found that both T- and NK-LGLL cells strongly expressed CD95, an apoptosis related protein. Anit-CD95 did not induce apoptosis, but suppressed proliferation induced by IL-2 or anti-CD3. These results suggest that CD95-CD95 ligand system is involved in the slow cell growth characteristic of chronic LGLL. (3) CD4+CD8+ double positive (DP) cases are rarely seen in LGLL, and the physiologic counterpart of the leukemic cells has not been determined yet. We found that the DP-LGLL had alpha alpha type in the CD8 subunit and did not express RAG-1, these findings being characteristic of peripheral T cells. We also found that they expressed IL-4 mRNA and secreted IL-4 on activation. These results strongly suggest that DP-T-LGLL represents an expansion of a rare subset of peripheral DP-T cells, possibly derived from IL-4 activated CD4 single positive T cells.
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PMID:[Large granular lymphocyte leukemia]. 893 81

CD95 (Fas)/CD95 ligand (CD95 L)-mediated apoptosis is thought to be involved in the delayed progression of murine AIDS (MAIDS) induced by LP-BM5 murine leukemia virus (MuLV). We show evidence of apoptosis in lymphocytes of Peyer's patches (PP) at the early stage of MAIDS. Both T and B cells in PP expressed CD95 at the early stage of MAIDS and decreased in number thereafter. The decrease in T cells was not evident in CD95-mutated lpr mice with MAIDS, suggesting that CD95/CD95 L interaction is involved in the apoptosis of T cells in PP during the course of MAIDS. On the other hand, the number of B cells was also decreased in PP of lpr mice with MAIDS. The proliferative ability of B cells in PP of MAIDS mice in response to immunoglobulin M cross-linking or lipopolysaccharide was severely impaired, while the B cells normally proliferated in response to anti-CD40 monoclonal antibody. These findings imply that aberrantly activated B cells in PP undergo apoptosis independently of the CD95/CD95 L system during the course of infection with MAIDS virus.
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PMID:Apoptosis by CD95 (Fas)-dependent and -independent mechanisms in Peyer's patch lymphocytes in murine retrovirus-induced immunodeficiency syndrome. 897 Oct 21

Apoptotic cell death is induced by the cross-linking of Fas/APO-1 receptor (CD95) in acute myelogenous leukaemia (AML) cells. Since CD95 ligand (CD95L) is expressed on interleukin-2 (IL-2)-activated T cells, we investigated the involvement of CD95-CD95L pathway in T cell-mediated cytotoxicity against AML cells. Activated CD8+ T cells could efficiently kill a parental CD95-sensitive AML cell line, MML-1 and, to a lesser extent, a CD95-resistant clone, MML-1R. Neither MML-1 nor MML-1R cells were killed by activated CD4+ T cells. The blocking monoclonal antibody (MoAb) against CD95, ZB4, caused a significant inhibition of T-cell-mediated cytotoxicity against MML-1 cells but not against MML-1R cells. Interestingly, MML-1 cells underwent the classic nuclear morphologic changes and DNA fragmentation characteristic of apoptosis when cultured with activated T cells. Enumeration of apoptotic and necrotic nuclei showed that both apoptosis and necrosis were induced in MML-1 cells, whereas necrosis was exclusively observed in MML-1R cells. Apoptosis of MML-1 cells was completely blocked in the presence of ZB4 MoAb. Similarly, blocking by ZB4 MoAb significantly inhibited T-cell-mediated lysis of fresh AML cells in a CD95-sensitive group, but not in a CD95-refractory group. In addition CD8+ T cells expressed CD95L mRNA more abundantly than CD4+ T cells upon activation by IL-2. These findings suggest that T-cell-mediated cytotoxicity against AML cells requires participation of CD95-CD95L pathway for cytotoxic signal transduction leading to target apoptosis.
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PMID:Fas/APO-1 (CD95)-mediated cytotoxicity is responsible for the apoptotic cell death of leukaemic cells induced by interleukin-2-activated T cells. 901

Cross-linkage of the CD95 (FAS/APO-1) antigen is responsible for the induction of programmed cell death or apoptosis in a variety of normal and malignant cells of the haemopoietic system. In order to evaluate predominant expression of the CD95 gene in a cell lineage-specific manner, we have determined the CD95 expression patterns in cell lines of myeloid, T-, pre-B- or B-cell origin as well as those established from Hodgkin's disease (HD). Our results reveal constitutive transcriptional activation of the CD95 gene in all cell lines derived from the lymphoid and myeloid lineages. Despite the ubiquitous expression of CD95 transcripts in haemopoietic cells, the corresponding protein was undetectable in 2/5 cell lines derived from Burkitt lymphomas and 6/16 leukaemia cell lines of the megakaryocytic or monocytic lineage. In an effort to identify apoptosis-resistant cell lines resulting from mutations in the death-signalling domain of CD9 5 or from defects in the apoptotic pathway or in survival programmes, we applied a CD95-mediated apoptosis assay. However, 21/38 CD95-expressing cell lines were sensitive upon induction with an anti-CD95 antibody whereas the remaining cell lines (predominantly of myeloid derivation) were resistant to antibody-induced cell death. Resistance to CD95-mediated apoptosis was not due to mutations within the CD95 open reading frame as confirmed by a combined reverse transcription PCR sequencing method. Five myeloid out of 13 tumour lines with the apoptosis-resistance phenotype analysed showed programmed cell death, when protein synthesis was blocked by treatment with cycloheximide prior to CD95-mediated induction. These data suggest an active cellular mechanism for the maintenance of an apoptosis-resistant phenotype. Elucidating the steps in such an active process of resistance to apoptosis might be expected to provide new approaches for therapeutic intervention in certain tumours.
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PMID:Expression and function of CD95 (FAS/APO-1) in leukaemia-lymphoma tumour lines. 905 67


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