Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antigen defined by the monoclonal antibody anti-Fas can mediate apoptosis, is associated with the receptor for tumor necrosis factor, and is expressed on a limited number of human tissues. In this study we analyzed the expression of Fas on primary human leukemic cells and on mononuclear cells from other hematologic disorders. A total of 95 samples of blood or bone marrow were studied by indirect immunofluorescence. These samples included the normal controls, 47 cases of acute myelogenous leukemia (AML), 11 cases of acute lymphoblastic leukemia (ALL), 21 cases of leukemic lymphoma, seven cases of chronic myelogenous leukemia (CML), five cases of plasma cell leukemia or multiple myeloma, and five cases of myelodysplastic or myeloproliferative syndromes. Normal controls were negative without exception. Among AML, 13/47 cases (28%) were positive; among ALL, 1/11 cases (9%) was positive; among leukemic lymphomas, 3/21 cases (14%) were positive. In a case of plasma cell leukemia which strongly expressed the Fas antigen, we demonstrated that the antibody mediates cell lysis, which was synergistically enhanced by the addition of rabbit complement. In patients with AML, Fas positivity had no obvious clinical relevance. Taken together, our results show that approximately 30% of cases of AML and occasionally other leukemias express the Fas antigens, whereas normal controls are negative in our test system. These findings may be useful in the treatment of refractory leukemias or may permit the purging of autologous transplants.
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PMID:Expression of the Fas antigen on primary human leukemia cells. 753 54

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

Relatively little is known about oncogene involvement in the regulation of Fas-mediated apoptosis. Inhibition of Fas-induced cell death by the bcl-2 oncogene has been demonstrated to be only partial. In light of a growing body of evidence for the Abl kinase as a negative regulator of cell death, we sought to determine whether Abl expression could protect against Fas-mediated cell death. To address this question, we utilized two separate strategies. In the first, we expressed human Fas in K562, a chronic myelogenous leukemia cell line, which constitutively expresses bcr-abl and examined the effects of Fas ligation in these cells. Fas-positive K562 transformants (K562.Fas) were found to be protected against Fas-mediated cell death. However, down-regulation of Bcr-Abl protein levels in K562.Fas cells using antisense oligonucleotides targeted to bcr-abl mRNA rendered these cells highly susceptible to Fas-induced death. In the second approach we utilized a Fas-positive HL-60 cell line, which we transfected with a temperature-sensitive mutant of v-Abl. HL-60.v-Ablts transfectants were found to be protected from Fas-induced apoptosis at the permissive but not the restrictive temperature for the Abl kinase. Taken together, these observations identify the Abl kinase as a negative regulator of Fas-mediated cell death. Since Abl was also found to block apoptosis mediated by ceramide, a recently proposed downstream effector of the apoptotic pathway initiated by Fas, we propose that Abl exerts its protective effects downstream of the early Fas-initiated signaling events.
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PMID:Regulation of the Fas apoptotic cell death pathway by Abl. 754 82

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.
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PMID:Soluble FAS (CD95) is not elevated in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. 875 76

Interferon-alpha (IFN-alpha) is an established treatment for chronic myelogenous leukemia (CML) in chronic phase, but the mechanism of its antileukemic activity is not clear. One possible mechanism of action might include the induction of apoptosis, and especially Fas-mediated cell killing may play an important role in the elimination of malignant cells. We investigated Fas receptor (Fas-R) expression and the consequences of Fas-R triggering in CML patients. Using two-color flow cytometry, we found a significantly higher number of Fas-R-expressing CD34+ cells in the bone marrow (BM) of CML patients compared with normal subjects. We have previously shown that IFN-gamma induces Fas-R expression on CD34+ cells; in this study, we investigated whether IFN-alpha induces Fas-R expression on CML progenitor cells. Dose-dependent induction of Fas-R expression was observed after IFN-alpha stimulation of CD34+ cells from CML BM. In methylcellulose culture, IFN-alpha alone at a therapeutic concentration showed only marginal antiproliferative effects on both normal and CML BM progenitors. In contrast, a Fas-R agonist, the anti-CD95 monoclonal antibody CH11, inhibited colony formation from normal progenitors, and the inhibition was even stronger on CML progenitors. When CML BM cells were cultured in the presence of IFN-alpha, Fas-R-mediated inhibition of colony growth was potentiated in a dose-dependent fashion, consistent with IFN-alpha induction of Fas-R expression. This functional effect did not require the presence of accessory cells, since similar results were obtained with purified CD34+ cells. In suspension cultures, we demonstrated that suppression of CML hematopoiesis by IFN-alpha and Fas-R agonist was exerted through Fas-R-mediated induction of apoptosis. Our findings suggest that the Fas-R/Fas-ligand system might be involved in the immunologic regulation of CML progenitor growth and that its effect can be amplified by IFN-alpha.
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PMID:Involvement of Fas-mediated apoptosis in the inhibitory effects of interferon-alpha in chronic myelogenous leukemia. 902 27

The human myeloid leukemias are a diverse group of disorders characterized by massive clonal expansion of myeloid cells showing variable degrees of differentiation block. Leukemic dendritic cells were generated in culture from chronic myelogenous leukemia (CML). These were used to stimulate autologous T cells to develop leukemia-specific cytotoxicity. Available data suggest that the cells responsible for the cytolytic activity are at least in part CD8+ and HLA restricted in their function. Additional data suggest that some anti-CML cellular activity may be Fas mediated. T-cell receptor studies provide evidence for an oligoclonal response implying a recognition of a limited number of antigens. We have used culture techniques similar to those used for CML to study the ability of AML cells to differentiate toward dendritic cells. Four of five patients have shown acute leukemia-derived dendritic cells. This work offers an avenue for the development of novel strategies for the control of human myeloid leukemias.
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PMID:Human leukemia-derived dendritic cells: ex-vivo development of specific antileukemic cytotoxicity. 941 54

In order to clarify the action of the bcr-abl, a growth factor dependent human leukemic cell line (HSM-911) was transfected with p210bcr-abl or bcr-v-abl by electroporation. The cells transfected with bcr-v-abl, but not the cells transfected with p210bcr-abl, became growth factor independent. Some clones of the cells transfected with p210bcr-abl demonstrated cellular maturation (nuclear segmentation, becoming positive for naphthol ASD chloroacetate esterase, the disappearance of CD34 expression and the appearance of glycophorin A and CD10 expression). Moreover, these clones transfected with p210bcr-abl demonstrated apoptosis (increased expression of Fas and DNA ladder formation suggesting apoptotic DNA fragmentation). These findings demonstrated the different actions of p210 bcr-abl and bcr-v-abl, the former of which gave the cells the characteristics of maturation like the cells from chronic myelogenous leukemia, and the latter of which rendered the cells grow autonomously.
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PMID:Effects of transfection of p210bcr-abl and bcr-v-abl into the factor-dependent human leukemia cell line HSM-911. 944 46

Fas-R is expressed constitutively in CD34(+) cells of patients with chronic myelogenous leukemia (CML); Fas-R triggering results in decreased proliferation rate due to apoptosis of clonogenic cells. We have already shown that alpha-interferon (IFN-alpha) enhances Fas-R expression on CML progenitor cells, thus increasing their sensitivity to Fas-R agonists. Although it appears that IFN-alpha can prime CML cells for the effects of Fas, the response to IFN-alpha in vivo is not a constant feature in CML patients. We studied the mechanisms of Fas-mediated apoptosis in 11 patients suffering from CML in chronic phase and tried to see whether there was a correlation between in vitro inducibility of apoptosis in CD34(+) CML cells after Fas-R triggering and the clinical response to IFN-alpha. After priming with IFN-alpha, Fas triggering resulted in in vitro suppression of hematopoietic cell growth in seven of eight patients who had optimal hematologic response to IFN-alpha; in the same conditions, no inhibitory response to Fas-R agonist was observed in cells from three of three patients who proved to be poor responders to IFN-alpha. In responders to IFN-alpha, Fas-R agonist induced dose-dependent apoptosis of CD34(+) cells; this effect was associated with a decrease in the bcr/abl protein level. In cells derived from patients with a poor response to IFN-alpha, the rate of apoptosis in culture remained unchanged in the presence of Fas-R agonist and no bcr/abl downmodulation was observed. Finally, we measured bcr/abl mRNA by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and found that decreased bcr/abl protein after Fas triggering was not associated with decreased amounts of specific mRNA, a finding which is consistent with a posttranscriptional regulation of the bcr/abl protein expression. It appears that Fas-mediated downmodulation of p210 bcr/abl restores susceptibility to apoptosis of CML cells; in addition, in vitro studies on CML cells may predict response to IFN-alpha treatment.
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PMID:Fas-mediated modulation of Bcr/Abl in chronic myelogenous leukemia results in differential effects on apoptosis. 968 Mar 67

Drug resistance is a common cause of treatment failure in oncology. In addition to the resistance caused by over-expression of p-glycoprotein and similar molecules other mechanisms are involved in the selection or induction of drug resistant tumor cells. In this study, we characterized a CML cell line made resistant to cyclophosphamide (KBM7-B5-1803) further for the expression of apoptosis promoting and inhibiting molecules. We found that KBM7-B5-1803 has a 3 4-fold over-expression of the receptor CD95 (Fas/Apo-1) compared with the parent line. The regulation of CD95 by cytokines was comparable to other types of cells. Despite the inducibility and over-expression of CD95, CD95 failed to trigger apoptosis in both the parent and the drug resistant line. The drug resistant line has a particular pattern of the expression of bcl-2 family members: bcl-2 protein and message were expressed to a similar extent, however, compared with the parent line, the message for bclx short was decreased. P-glycoprotein was not expressed in either cell line. Taken together we show here in a leukemia cell line that the phenotype of cyclophosphamide resistance is associated with a particular pattern of apoptosis-related molecules.
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PMID:Further characterization of cyclophosphamide resistance: expression of CD95 and of bcl-2 in a CML cell line. 978 11

Fas antigen, also termed APO-1 or CD95, is a transmembrane protein and a member of the tumor necrosis factor receptor/nerve growth factor receptor superfamily which mediates apoptosis upon oligomerization. The Fas/Fas ligand system is considered to be a key regulator of apoptosis. Recently, we have demonstrated that Fas antigen expression is induced by low-dose irradiation of some types of lymphomas, and we also demonstrated that irradiation-induced Fas antigen expression increased with the passage of time until peaking at 48 h after irradiation in CML-C1, CML-C2, DL-40, and DL-95 cell lines. In this study, we also examined the potential cytotoxicity of Fas ligand peptide against several types of lymphoma/leukemia cell lines that showed induction of Fas antigen expression under irradiation. Flow cytometry analysis was performed at 6, 24 and 48 h after irradiation. Samples (1 x10(6) cells/ml) from irradiated and non-irradiated cells of each cell line were incubated with or without 5 microg/ml of Fas ligand peptide for 2 h at 37 degrees C in a humidified atmosphere of 5% carbon dioxide (CO2) in air. The killing effect of Fas ligand against cell lines of CML-C1, DL-40, and DL-95 were clearly identified as the percentage of cells with Fas antigen expression induced by irradiation. Concerning HD-70 cell line, for which soluble Fas antigen has been identified, the killing effects were clearly observed in samples pre-treated with PBS washings. To our knowledge, this is the first report describing a possible application of the Fas/Fas ligand system in treatment of certain types of malignancies in which Fas antigen is inducible by irradiation.
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PMID:Cytotoxicity of Fas ligand against lymphoma cells with radiation-induced Fas antigen. 985 30


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