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 molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are only partially understood. In chemosensitive leukemias and solid tumors, anticancer drugs have been shown to induce apoptosis. We previously identified activation of the CD95 (APO-1/Fas) receptor/CD95 ligand (CD95/CD95-L) system as a key mechanism for drug-induced apoptosis. Here, we show that therapeutic concentrations of doxorubicin, methotrexate and cytarabine also induce apoptosis via activation of the CD95 system in primary leukemia cells in vivo. CD95-resistant and doxorubicin-resistant leukemia and neuroblastoma cells display cross-resistance for induction of cell death. Down-regulation of CD95 expression was found in drug-resistant and CD95-resistant cell lines. Furthermore, up-regulation of CD95-L, previously shown to mediate drug-induced apoptosis in a variety of tumor cells, was completely blocked in doxorubicin-resistant cells. The prototype caspase (ICE/Ced-3 protease) substrate, poly(ADP-ribose)polymerase (PARP), was cleaved in sensitive, but not in resistant tumor cells following CD95 triggering or drug treatment. Since failure to activate CD95-L was not due to decreased drug uptake or increased drug efflux, non-multi-drug resistance (non-MDR) mechanisms are involved in this type of resistance. These findings suggested that an intact CD95 system plays a key role in determining sensitivity or resistance towards anticancer therapy.
Leukemia 1997 Nov
PMID:Deficient activation of the CD95 (APO-1/Fas) system in drug-resistant cells. 936 15

Fas ligand (FasL) is capable of inducing apoptosis of lymphoid cells by cross-linking with its natural receptor, Fas. We aimed to investigate the possible role of the Fas/FasL-mediated apoptosis in the development of human lymphomas. FasL mRNA was detected by reverse transcriptase-polymerase chain reaction in 38 out of 63 lymphoma biopsy specimens representative of various subtypes of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease. FasL was co-expressed with Fas mRNA in most cases. Flow cytometry (FACS) analysis showed a bright FasL staining in 31% to up to 75% of the total cell population from 14 out of 16 samples; the presence of the FasL protein was confirmed by Western blotting. Dual-color FACS analysis showed that FasL was expressed by T cells in B-NHLs and T-NHLs. A significant percentage of B cells in various B-NHLs also stained positively for FasL. Freshly separated neoplastic B cells from three FasL+ and one FasL- B-NHLs displayed a relative resistance to Fas-mediated apoptosis, when compared to reactive T cells isolated from the same tissue samples. In contrast, the sensitivity to Fas-mediated killing of the T cells isolated from two FasL+ T-NHLs was not uniform. These data show that (1) FasL is expressed in both neoplastic and reactive cells from a significant proportion of lymphoma cases, and (2) that the intratumoral FasL+/Fas+ reactive T cells are more sensitive to Fas-induced apoptosis than the neoplastic FasL+/Fas+ malignant B cells. A putative defect in the Fas/FasL pathway may thus favor the development of malignant B cell populations.
Leukemia 1997 Nov
PMID:Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis. 936 20

mRNA expression of Fas (CD95)-associated proteins [Fas-associating protein with death domain (FADD), receptor-interacting protein (RIP), and Fas-associated phosphatase-1 (FAP-1)] has been investigated in 26 Fas-positive human leukaemia/lymphoma cell lines. Reverse transcriptase-polymerase chain reaction analysis revealed that FADD and RIP mRNA were invariably expressed in both Fas-sensitive and Fas-insensitive cell lines. However, FAP-1 mRNA was detected in only 11 of 26 cell lines. Interestingly 7/14 cell lines in the Fas-sensitive group were positive for FAP-1 mRNA expression. 8/12 cell lines in the Fas-refractory group did not express FAP-1 mRNA, but half of these cell lines were susceptible to tumour necrosis factor alpha-induced growth inhibition. These findings suggest that the presence or absence of FAP-1 mRNA expression did not always correlate with relative sensitivity of Fas-mediated growth inhibition. Furthermore, it is assumed that leukaemia/lymphoma cells could possess structural or functional defects of Fas or Fas-associated proteins resulting in the failure to trigger apoptotic cell death.
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PMID:mRNA expression of Fas receptor (CD95)-associated proteins (Fas-associated phosphatase-1/FAP-1, Fas-associating protein with death domain/FADD, and receptor-interacting protein/RIP) in human leukaemia/lymphoma cell lines. 937 49

The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system. After drug treatment, a strong increase of caspase activity was found that preceded cell death. Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin. The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis. Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells.
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PMID:Cross-resistance of CD95- and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases). 937 93

Clinical studies of bone marrow transplantation (BMT) suggest that the immune system contributes to the eradication of acute myeloid leukemia (AML). A recent study also showed that the Fas (CD95/APO1) mediates apoptotic signal from cytotoxic T lymphocytes. Sixty-four patients with AML were studied for the expression of Fas in the context of CD34 and CD38 coexpression. The clinical relevance of Fas expression and function on AML was also investigated. Fas was expressed on 2% to 98% of AML cells (2% to 20% in 11 patients, 20% to 50% in 20 patients, 50% to 80% in 24 patients, and 80% to 98% in nine patients). Only 44.4% of patients with AML M1 (French-American-British [FAB] classification) were Fas+ (>/=20% of leukemia cells expressed Fas), whereas 89.1% of patients with AML M2, M3, M4, M5 were Fas+ (P < .01). Among 43 CD34+ patients (>/=20% leukemia cells were CD34+), 34 were Fas+, and 19 of 21 CD34- patients were Fas+ (P = NS). Thirteen cases were studied for their expression of Fas in the context of CD34 and CD38 using three-color analysis. Fas is expressed at a high level in the gated CD34+CD38+/- and CD34+CD38+ population. In 10 AML samples, Fas was expressed at a higher level in CD34+/CD38+ population than in CD34+/CD38+/- or CD34- cell populations. Fas-induced apoptosis by anti-Fas monoclonal antibody (MoAb) was determined by morphologic features and colorimetric DNA fragmentation assay. Induction of apoptosis was found in 14 of 24 cases. However, no statistically significant correlation was observed between Fas expression and induction of apoptosis. Leukemia colony-forming unit assays suggested that in some cases, Fas-induced apoptosis occurred in the clonogenic cell populations. Parameters such as laboratory and clinical data at initial diagnosis were correlated with Fas expression and only response to initial induction chemotherapy showed significant correlation with Fas expression (P < .05). We conclude that the majority of AML cells exhibit variable expression of Fas, and apoptosis could be induced by anti-Fas MoAb in some cases. Our results suggest the Fas-mediated apoptosis may be clinically relevant, whereas the issue of clonogenic leukemia cells and Fas expression needs further studies.
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PMID:Functional expression of Fas (CD95) in acute myeloid leukemia cells in the context of CD34 and CD38 expression: possible correlation with sensitivity to chemotherapy. 938 7

Two distinct human diseases have been described in association with human T cell lymphotropic virus type I (HTLV-I) infection: adult T cell leukaemia and tropical spastic paraparesis/HTLV-I-associated myelopathy. Although comprehensive understanding of specific mechanisms underlying pathogenesis of either disease has not yet been achieved, the viral regulatory protein Tax is believed to play a significant role. Previous studies demonstrated the potential of Tax to transform host cells. Here, it is shown that the Tax transactivator has in addition the potential to induce T cell death by apoptosis. Using an inducible system (Jurkat cell line JPX-9), significant apoptotic cell death upon Tax expression was observed. In an attempt to detect the cellular genes mediating this effect, it was found that induction of Tax was associated with marked upregulation of the Fas ligand (FasL) gene. Tax-induced apoptosis was inhibited when the Fas/FasL pathway was interrupted by YVAD-cmk, the inhibitor of ICE-like proteases. Transient expression experiments provided additional support for the putative role of endogenous FasL in Tax-induced apoptosis. Upon cotransfection with Tax-expressing plasmid, the transcriptional activity of the FasL promoter was found to be significantly upregulated in Jurkat cells and several other cell lines, as measured by reporter gene expression. Furthermore, cotransfection using different Tax mutants demonstrated that both CREB and NF-kappaB activation domains of Tax protein were required for the transactivation to take effect.
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PMID:Role of the Fas/Fas ligand pathway in apoptotic cell death induced by the human T cell lymphotropic virus type I Tax transactivator. 940 Sep 78

We compared two methods to stain apoptotic cells, one using terminal deoxynucleotidyl transferase (TDT), the other DNA polymerase I, using leukemia cell lines treated with anti-Fas monoclonal antibody (MAb). Both TDT and polymerase I strongly reacted with fragmented nuclei of apoptotic MOLT-16 and Jurkat cells, but only polymerase I strongly reacted with nonfragmented nuclei of early apoptotic cells. Anti-Fas MAb-treated MOLT-4 cells showed morphological changes corresponding to early apoptosis and were strongly positive for polymerase I only. MOLT-16 and Jurkat cells treated with anti-Fas MAb and inhibitors of endonuclease and poly(ADP-ribose) polymerase showed the morphology of early apoptosis but were not strongly stained by TDT. Because DNA polymerase I has nick-translation activity, it is possible that DNA polymerase I reaction is positive in early apoptotic cells by detecting single-strand DNA cleavage, which occurs before extensive oligonucleosomal DNA cleavage and late morphological changes of apoptosis in leukemia cell lines. Although TDT is widely used to stain apoptotic cells, DNA polymerase I may be more applicable in special cases of apoptosis, in which cells undergo single-strand rather than double-strand DNA breaks. However, the procedure has limitations, such as the necessity to use cell smears for comparison with the TDT reaction. (J Histochem Cytochem 46:85-90, 1998)
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PMID:Comparison of two methods of staining apoptotic cells of leukemia cell lines. Terminal deoxynucleotidyl transferase and DNA polymerase I reactions. 940 97

It has recently been proposed that doxorubicin (DOX) can induce apoptosis in human T-leukemia cells via the Fas/FasL system in an autocrine/paracrine way. We show here that treatment of Jurkat cells with either anti-Fas antibodies, anthracyclin drugs or actinomycin D induces the activation of CPP32 (caspase-3) and apoptosis. However, DOX treatment did not induce the expression of membrane FasL or the release of soluble FasL and co-incubation with blocking anti-Fas antibodies prevented Fas-induced but not DOX-induced apoptosis. All the morphological and biochemical signs of apoptosis induced by anti-Fas or DOX can be prevented by Z-VAD-fmk, a general caspase inhibitor. DEVD-cho, a specific inhibitor of CPP32-like caspases which completely blocks Fas-mediated apoptosis, prevented drug-induced nuclear apoptosis but not cell death. We conclude that: (i) DOX-induced apoptosis in human T-leukemia/lymphoma is Fas-independent and (ii) caspase-3 is responsible of DOX-induced nuclear apoptosis but other Z-VAD-sensitive caspases are implicated in cell death.
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PMID:Doxorubicin-induced apoptosis in human T-cell leukemia is mediated by caspase-3 activation in a Fas-independent way. 940 52

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

Previously, we reported that a strain of severe combined immunodeficient (SCID) mice, namely SCID-bg, spontaneously develop CD4+CD8+ double positive (DP) thymocytes despite their scid mutation. In the present study, we intend to further characterize the DP thymocyte population in SCID-bg mice with Southern hybridization and flow cytometry. Southern hybridization analyses of sorted DP thymocytes in SCID-bg mice showed rearrangement of T cell receptor (TCR) beta and TCR gamma gene segments, although the expression of TCR beta and gamma delta TCR molecules was absent. The phenotype of the DP thymocytes in SCID-bg mice was CD44- heat-stable antigen (HSA)+CD25-, and they did not express CD69. Interestingly, the expression of thymus leukaemia (TL) antigen was observed in the DP thymocytes of SCID-bg mice but not in their CD4-CD8- double negative (DN) fraction. Fas expression was higher and bcl-2 expression was down-regulated in the DP thymocytes as compared to the DN thymocytes in SCID-bg mice, suggesting that they are not immortalized cells having escaped from apoptosis. Taken together, these results show that the phenotype of the DP thymocytes in SCID-bg mice is similar to that of the earliest phase of the DP thymocytes in normal mice, although the expression of the molecules in the pre-TCR complex is absent.
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PMID:Characterization of CD4+CD8+ thymocytes observed in SCID-bg mice. 942 95


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