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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have suggested that wild-type p53 blocks cell cycle progression near the G1-S boundary and is involved in both differentiation and apoptosis in many types of cells including cancer cells. p53 expression is enhanced upon DNA-damaging apoptotic stimuli while Fas/Apo-1, a member of the tumor necrosis factor receptor family expressed on cell surface, transduces a signal for apoptosis upon specific ligand or antibody engagement. We demonstrated that stable transfection of the wild-type p53 gene under the control of CMV promoter induced differentiation and apoptosis under restricted conditions in cancer cells, and often caused sensitization of p53-transfected cells to Fas/Apo-1 signal. To investigate the interaction between two major apoptotic pathways involving p53 and Fas/Apo-1 we have established a system that allows to induce wild-type p53 overexpression and apoptosis in cancer cells upon treatment with anti-Fas antibody. The system also allows to investigate other factors interacting with p53 and Fas/Apo-1, and should provide a clue to understanding the biological and biochemical aspects of apoptosis.
Leukemia 1997 Apr
PMID:Role of p53 tumor suppressor gene and Fas/Apo-1 in induction of apoptosis and differentiation of cancer cells. 920 81

Fas, also designated as Apo-1 and CD95, is a cell membrane receptor (mFas) involved in apoptotic cell death. A soluble form (sFas) lacking the transmembrane domain due to alternative splicing has been isolated. Abnormal expression of sFas and mFas is likely to be involved in lymphoproliferative disorders and auto-immune diseases. Adult T-cell leukemia (ATL) caused by human T-cell-leukemia virus type-1 (HTLV-1) is well known to be a T-cell neoplasm with strong mFas expression, suggesting a role of Fas in the pathology of the disease. We examined protein and mRNA expression of the 2 isoforms of Fas in fresh ATL cells and ATL cell lines. In general, mFas was strongly expressed in ATL cells, and sFas levels in sera were high, especially in malignant ATL. However, expression of the isoforms in some cases of ATL varied; there was no mFas expression on the cell surface and sFas levels were high in serum. In contrast, all ATL cell lines examined showed strong mFas expression and scarce production of sFas in the supernatant, corresponding to strong expression of full-length Fas mRNA and weak to negative expression of alternatively spliced mRNA lacking the transmembrane domain. Our findings indicate that the mode of expression of Fas isoforms in ATL cells is not always homogenous and that Fas may play a role in the malignant behavior and oncogenesis of ATL.
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PMID:Soluble and membrane isoforms of Fas/CD95 in fresh adult T-cell leukemia (ATL) cells and ATL-cell lines. 921 33

To clarify whether apoptosis is involved in endometriosis, we obtained eutopic endometrial tissues along with endometriotic tissues from the uterus (adenomyosis) (n = 12) and from the ovary (n = 12) from patients undergoing gynaecological surgery. Apoptosis-induced DNA fragmentation was detected by the TdT-mediated dUTP-biotin nick-end labelling method, and immunostaining with a monoclonal antibody against the Fas, Le(y) or B-cell leukaemia/lymphoma-2 (bcl-2) was also performed using the same tissue section. Analysis showed that apoptosis was occurring in all the samples of ovarian endometriotic tissue but in only two of the 12 adenomyotic and in five of the 24 eutopic endometrial tissue samples. In none of these cases was apoptosis correlated with phases of the menstrual cycle. The expression of bcl-2 in the eutopic endometrial and adenomyotic tissues was limited to the proliferative phase, and was observed in only one of the 12 cases of ovarian endometriosis. Fas and Ley were expressed randomly across a wide range in both the eutopic and ectopic endometrial tissues. These results suggest that the features of ovarian endometriosis are different from those of adenomyosis and eutopic endometrium in terms of the involvement of apoptosis. In addition, the regulatory mechanism involved in ovarian endometriosis may differ from that in other endometrial cells.
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PMID:Detection of apoptosis in human endometriotic tissues. 923 97

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

CD95 (Fas/APO-1) is a cell surface receptor able to trigger apoptosis in a variety of cell types. The expression and function of the CD95 antigen on leukemic blasts from 42 patients with B lineage and 53 patients with T lineage acute lymphoblastic leukemia (ALL) were investigated using immunofluorescence staining and apoptosis assays. The CD95 surface antigen was expressed in most ALL cases, with the T lineage ALL usually showing a higher intensity of surface CD95 expression as compared with the B lineage ALL cells (relative fluorescence intensity, RFI: 4.8 +/- 0.47 vs 2.2 +/- 0.23, respectively, P < 0.01). Functional studies disclosed that upon oligomerization by anti-CD95 monoclonal antibodies the CD95 protein was either not able to initiate apoptosis of leukemic cells (75% of cases) or induced low rates of apoptosis (20% of cases). Only in 5% of cases did the apoptosis rate exceed the 20% level of the CD95-specific apoptosis. Most of the CD95-sensitive cases were found among T lineage ALLs (38% of T lineage vs 10% of B lineage ALLs). Overall, the extent of CD95-induced apoptosis did not correlate with the expression level of CD95. Similarly, no significant correlation between expression level and functionality of CD95 in human leukemia cell lines of B and T cell origin could be observed. Bcl-2 protein has been associated with prolonged cell survival and has been shown to block partially CD95-mediated apoptosis, but for ALL cells no correlation between bcl-2 expression and spontaneous or CD95-mediated apoptosis could be found. The results obtained in this study indicate that, despite constitutive expression of CD95, the ALL cells are mainly resistant to CD95-triggering. More detailed investigations of the molecular mechanisms involved in the intracellular apoptotic signal transduction, such as interactions of the bcl-2 and the other members of the bcl-2 family, and functionality of the interleukin-1beta converting enzyme (ICE) like-proteases, may give new insights into key events responsible for the resistance or sensitivity to the induction of apoptosis in acute leukemia.
Leukemia 1997 Aug
PMID:Differential CD95 expression and function in T and B lineage acute lymphoblastic leukemia cells. 926 77

A human eosinophilic leukemia cell line, EoL-1, stopped proliferating at the G1 phase, differentiated into eosinophilic granule-containing cells, and died by apoptosis when stimulated with dibutyryl cyclic AMP (dbcAMP). To clarify the effects of dbcAMP, the effects of butyrate and cAMP-increasing reagents, prostaglandin E2 (PGE2) and forskolin, on EoL-1 cellular differentiation and apoptosis were examined and compared. PGE2 and forskolin but not butyrate induced differentiation to eosinophilic granule-containing cells, suggesting that cAMP played a primary role in eosinophilic differentiation of EoL-1 cells. PGE2, forskolin and butyrate, when used alone, did not induce apoptosis of EoL-1 cells significantly at the concentrations used, but sequential stimulation of EoL-1 cells with the cAMP-increasing reagents and butyrate showed that butyrate induced further maturation and apoptosis of cAMP-induced eosinophilic granule-containing cells. These results showed that cAMP and butyrate have different effects on eosinophilic differentiation and apoptosis of EoL-1 cells. The cAMP-increasing reagents and butyrate also showed different effects on expression of members of the bcl-2 family; PGE2 decreased bcl-2 and bax levels, whereas butyrate increased the bcl-2 level. PGE2 or PGE2+butyrate, but not butyrate alone, induced bcl-XS expression. EoL-1 cells constitutively expressed Fas and anti-Fas antibody induced EoL-1 cell death, but the Fas/Fas ligand system was not involved in dbcAMP-induced EoL-1 cell apoptosis. The EoL-1 cell line is thus a useful model in which to examine differentiation and apoptosis of eosinophilic leukemia cells.
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PMID:Different effects of cyclic AMP and butyrate on eosinophilic differentiation, apoptosis and bcl-2 expression of a human eosinophilic leukemia cell line, EoL-1. 926 64

Coculture of cytotoxic T cells (STIL-3 C5) derived from L8313 leukemic mice with hematopoietic supportive stromal cells (MS-5) resulted in the detachment of MS-5 cells from the culture dish, whereas helper T cells (STIL-3 DF) did not induce this detachment. The response of bone marrow (BM) adherent cells to the same treatment was similar to that of MS-5 cells. The detached cells were unable to proliferate further, and genomic DNA of these cells showed fragmentation, suggesting that hematopoietic stromal cells died of apoptosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that STIL-3 C5 cells, but not STIL-3 DF cells expressed perforin, granzyme A & B, and Fas ligand. Fas was expressed in MS-5, BM adherent cells, MS-K and NIH/3T3 cells, which do not support hematopoiesis. These data suggest that the aforementioned factors mediate induction of apoptosis in MS-5 cells induced by direct cell-to-cell interaction with STIL-3 C5. This may explain the mechanism responsible for the destruction of the hematopoietic microenvironment by cytotoxic T cells in L8313 leukemia, from which STIL-3 cells are derived; it also suggests that destruction of hematopoietic tissue may be caused by leukemic cytotoxic T cells in some cases of leukemia.
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PMID:Destruction of hematopoietic microenvironment by cytotoxic T cells. 929

Proteases that are members of the caspase (or interleukin-1beta converting enzyme (ICE)) protease family have been shown to be important mediators of apoptosis induced by Fas activation, neurotrophic factor withdrawal, and detachment from extracellular matrix. In this report we have investigated the potential importance of caspase proteases in apoptosis induced by multiple chemotherapeutic agents. Human T leukemic cells engineered to overexpress the cowpox virus CrmA protein, a direct and specific inhibitor of caspase proteases, were studied for their resistance to 1-beta-D-arabinofurasosyl-cytosine (Ara-C), etoposide (VP-16), doxorubicin (DOX), and cis-dichlorodiammine platinum (CP). Overexpression of CrmA dramatically inhibited drug-induced activation of caspases, as measured by processing of the inactive precursor form of caspase-3 and cleavage of caspase substrate proteins poly(ADP-ribose) polymerase (PARP) and lamin B. CrmA also significantly inhibited the kinetics of cell death induced by each of the four drugs. Moreover, when examined several days or weeks after initial exposure to drug, cultures of CrmA-expressing cells were found to have recovered and repopulated, whereas vector-transfected control cells did not. These studies demonstrate that caspase proteases play an important role in conferring sensitivity to multiple chemotherapy drugs, and that constitutive downmodulation of caspase activities can enhance chemoresistance.
Leukemia 1997 Oct
PMID:Inhibition of caspase proteases by CrmA enhances the resistance of human leukemic cells to multiple chemotherapeutic agents. 932 87

Vesnarinone is a positive inotropic agent used for treating congestive heart failure. We evaluated its ex vivo effects on myeloid leukemia cell lines and primary acute myelogenous leukemia cells. Vesnarinone inhibited the incorporation of radiolabeled thymidine by a myeloid cell line, HL60, in a dose-dependent manner at concentrations ranging from 0.1 to 30 microg/mL. A maximum 40% suppression was seen at a concentration of 10 microg/mL. Determination of viable cell counts by trypan blue dye exclusion method demonstrated vesnarinone to be cytocidal for HL60 cells. Vesnarinone induced DNA fragmentation as detected by electrophresis in HL60 cells after 72-hour culture; this effect was not inhibited by G-CSF. The apoptosis induced by vesnarinone was also detected by the in situ end-labeling method. Northern blot analysis showed a reduction of c-myc mRNA expression in HL60 cells by vesnarinone. However, immunostaining assay showed no change in the expression of Fas and Bcl-2 proteins. We next examined the effect of vesnarinone on primary myeloid leukemia cells derived from 10 patients: 3 cases of M1, 2 of M2, 3 of M3, 1 of M4, and 1 of M6, by the French-American-British classification. Vesnarinone inhibited the incorporation of thymidine in all cells, with a mean suppression of 58.1%. DNA electrophoresis showed induction of DNA fragmentation in cultured cells with vesnarinone for 72 hours in 8 of the 10 patients with primary leukemia. However, bone marrow mononuclear cells from healthy controls showed no growth suppression or DNA fragmentation in response to vesnarinone. These results suggest that vesnarinone may be useful in treating myeloid leukemia.
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PMID:Vesnarinone exhibits antitumor effect against myeloid leukemia cells via apoptosis. 932 55

Homeostasis of human B cell development is maintained by a complex network of cytoplasmic and surface expressed molecules. Abnormalities in this process may result in the expansion of malignant B cell precursors in B lineage acute lymphoblastic leukaemia (ALL). ALL cells share surface antigens with normal early precursor B cells. We have studied here the role of Fas/APO-1 (CD95) antigen on leukaemic precursor B cell line growth and survival, and the modulation of its effects by signals involved in normal early B cell development. Four ALL cell lines representative of the early steps of B cell differentiation are shown to express surface Fas/APO-1 (CD95) antigen and to undergo apoptosis in the presence of anti-Fas cross-linking antibodies. This effect is strongly enhanced when pre-B, but not pro-B cells, are pretreated with IL-7 but not with IL-2, IL-3, IL-4 or IL-10. Furthermore, pre-B cell death induced by anti-Fas antibodies in combination with IL-7 is increased upon pre-B receptor but not CD19 cross-linking. Bcl-2 and Bax protein expression is not influenced by IL-7 or pre-BR stimulation in either pro-B or pre-B cell lines. These results indicate that signals involved in normal early B cell development can modulate the Fas (CD95)-mediated apoptosis of leukaemic precursor B cells.
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PMID:IL-7 sensitizes human pre-B cells but not pro-B cells to Fas/APO-1 (CD95)-mediated apoptosis. 936 21


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