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 present study investigates the relationship between mitochondrial activity and the expression of the BCL-2 gene in a panel of six human and murine leukemia/lymphoma cell lines. The cell lines all contained normal glucocorticoid receptors but differed widely in sensitivity to dexamethasone, ranging from very sensitive S49 lymphoma to completely resistant HL-60 acute leukemia cells. In this panel, 10- to 15-fold differences in basal adenosine triphosphate (ATP) content and adenosine diphosphate (ADP)/ATP ratio were correlated with up to fivefold differences in bcl-2 protein (in human cells) and approximately 25-fold difference in bcl-2 mRNA content (all cell lines). Moreover, ATP content and BCL-2 gene expression were inversely correlated with glucocorticoid sensitivity and cell cycle length. In resistant cell lines, sensitivity to dexamethasone was restored by the mitochondrial inhibitors rotenone and meta-iodobenzylguanidine. This sensitization was not accompanied by detectable reductions in bcl-2 mRNA or protein content, suggesting that the inhibitors were capable of overriding BCL-2-mediated inhibition of apoptosis. Increased mitochondrial activity and (overexpressed) BCL-2 appeared closely related properties of glucocorticoid-resistant cells, sharing common cellular targets in hormone-induced apoptosis.
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PMID:BCL-2 expression and mitochondrial activity in leukemic cells with different sensitivity to glucocorticoid-induced apoptosis. 806 50

The bcl-2 gene becomes dysregulated in its expression in a wide variety of human cancers and has been shown to block both spontaneous and drug-induced cell death, thus conferring a selective survival advantage on malignant cells. The biochemical mechanism by which bcl-2 promotes cell survival remains enigmatic but appears to involve a downstream event in an evolutionarily conserved cell death pathway. Here we report that gene transfer-mediated increases in Bcl-2 protein levels in the human leukemia line Jurkat render these cells more resistant to induction of DNA fragmentation and cytolysis by a cloned T-cell. The killing mechanism used by these particular T-cells was consistent with apoptosis, as opposed to necrosis, in that DNA degradation occurred as a prelysis event. The findings raise the possibility that dysregulation of bcl-2 gene expression could play a role in the avoidance of immune surveillance mechanisms by cancer cells.
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PMID:Bcl-2 inhibits T-cell-mediated cytolysis of a leukemia cell line. 806 51

The Tax protein of human T-cell leukemia virus type I activates transcription of cellular and viral genes and can immortalize primary T lymphocytes. We have previously reported that the Tax protein transforms Rat-1 cells. Here we show that Tax-transformed Rat-1 cells detach from plates to undergo apoptotic cell death by serum deprivation. These cells exhibit DNA fragmentation into oligonucleosomal fragments and chromatin condensation. Constitutive expression of a proto-oncogene, bcl-2, effectively blocks Tax-mediated apoptosis caused by serum deprivation without affecting the levels of Tax expression and the transformed phenotype of the cells.
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PMID:The human T-cell leukemia virus type I Tax protein induces apoptosis which is blocked by the Bcl-2 protein. 815 96

Apoptotic cell death is physiological. Malignant cells often escape programmed cell death. Many genes that promote (p53) or antagonize (bcl-2, fes) apoptosis have been recognized. Apoptosis promoter genes can be activated by growth factor or hormone withdrawal in growth factor- or hormone-dependent tumor cells. Malignant cells acquiring apoptosis-resistance, still can be killed by cytotoxic lymphocytes releasing lymphotoxins. This phenomenon gives further support to the therapeutic use of activated and expanded lymphocyte populations and/or apoptosis-inducing cytokines. Chemotherapeutic agents (esp. topoisomerase inhibitors) frequently kill tumor cells by activating programmed cell death (PCD). Biologicals and chemotherapeutics may synergize in evoking apoptosis. We propose the cloning of apoptotic genes and their transfer by transfection in vivo into tumor cells. While transfection of genes into tumor cells in vitro is widely practiced, the lack of proper technology for transfection in vivo and the unknown aspects of apoptotic cell death are recognized.
Leukemia 1994 Apr
PMID:Apoptosis by genetic engineering. 815 15

Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein which can inhibit the onset of apoptosis induced by withdrawal of trophic factors or by antitumour drugs. In some malignant cells bcl-2 expression has been demonstrated to be regulated by specific trophic factors which act to suppress apoptosis. Here we have investigated the effect of exogenous and autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) on both bcl-2 expression and apoptosis in acute myeloid leukaemia (AML) cells. Blasts from 31 patients with AML were studied, this included 21 patients whose cells exhibited variable degrees of autonomous growth in culture and ten patients with non-autonomous growth. Blasts with autonomous growth expressed significantly higher levels of bcl-2 protein, the intensity of fluorescence expressed as soluble fluorochrome per cell was 40.9 +/- 3.6 x 10(3) (mean +/- SD); this compared with an intensity of bcl-2 expression of 19.3 +/- 2.4 x 10(3) for blasts with non-autocrine growth (p < 0.0001 by Mann-Whitney analysis). Blasts with non-autocrine growth rapidly lost viability following 48 h of culture due to the onset of apoptosis. In these cells apoptosis was suppressed by the addition of GM-CSF and bcl-2 protein expression was found to be significantly upregulated. In contrast blasts from patients with autonomous growth and autocrine GM-CSF production failed to show any features of apoptosis in culture. In these cells bcl-2 expression was significantly downregulated following neutralization of autocrine GM-CSF by antibodies. We conclude that bcl-2 expression in AML cells is regulated by GM-CSF, and suggest that the previously demonstrated negative prognostic effect of autocrine growth as a determinant of treatment outcome in AML is in part due to the effect of autocrine GM-CSF in upregulating bcl-2 expression.
Leukemia 1994 May
PMID:Regulation of Bcl-2 expression and apoptosis in acute myeloblastic leukaemia cells by granulocyte-macrophage colony-stimulating factor. 818 35

The p53 tumor suppressor gene product can induce apoptotic cell death through an unknown mechanism. Here we demonstrate that a temperature-sensitive p53 induces temperature-dependent decreases in the expression of the apoptosis-suppressing gene bcl-2 in the murine leukemia cell M1, while simultaneously stimulating increases in the expression of bax, a gene which encodes a dominant-inhibitor of the Bcl-2 protein. Mice deficient in p53 exhibit increases in Bcl-2 and decreases in Bax protein levels in several tissues as determined by immunohistochemical and immunoblot methods. The findings suggest a potential mechanism by which p53 regulates apoptosis, as well as responses to radiation and chemotherapeutic drugs in cancer.
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PMID:Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. 818 79

Bcl-2 is an inner mitochondrial membrane protein which blocks apoptosis. Although present in many B cells, the vast majority of follicular center cells do not have detectable bcl-2 protein. The bcl-2 gene is translocated in most conventional small cleaved follicular center cell (SCFCC) lymphomas (centroblastic/centrocytic) but not in centrocytic lymphomas (CC). The translocated gene in the SCFCC lymphomas leads to 'aberrant' bcl-2 expression by the neoplastic follicular center cells. The frequency with which the normal non-translocated gene is expressed in CC lymphomas is, however, not well documented. Paraffin sections from 22 cases of centrocytic lymphoma were therefore stained with an anti-bcl-2 antibody. Genotypic studies in 14 cases demonstrated bcl-1/PRAD1 (cyclin D1; CCND1) rearrangements in ten and bcl-2 rearrangements in none. All centrocytic lymphomas demonstrated bcl-2 protein expression in the majority of neoplastic cells. Negative staining residual follicular centers were identified in four cases emphasizing the mantle zone growth pattern of a subset of CC lymphomas. Expression of bcl-2 protein in the absence of bcl-2 gene rearrangement is a feature shared by centrocytic lymphomas and mantle zone cells. However, because this type of bcl-2 expression is not specific for B-cells of the mantle zone, it does not further elucidate the true cell of origin for the centrocytic lymphomas.
Leukemia 1993 Sep
PMID:Bcl-2 protein in centrocytic lymphoma; a paraffin section study. 837 94

Rearrangements of the BCL2 gene and expression of bcl-2 protein were analyzed in a series of 64 cases of follicular lymphomas in order to establish a relationship between the rearrangements and the protein overexpression. Of the 64 cases, 41 showed BCL2 rearrangement involving one of the three breakpoint clusters: 30 in mbr, eight in mcr, and three in vcr. A double rearrangement mbr+vcr was detected in two cases. Twenty cases with bcl-2 protein expression in tumor cells exhibited no apparent rearrangement, suggesting the possible existence of other mechanisms activating the gene. Interestingly, expression of the LMP1 protein, the Epstein-Barr virus (EBV) encoded gene, whose capacity to induce BCL2 has been recently demonstrated, was only found in 2/41 cases in which BCL2 was rearranged. These data suggest that EBV infection is not an important mechanism in the activation of BCL2 in follicular lymphoma.
Leukemia 1993 Mar
PMID:BCL2 gene activation and protein expression in follicular lymphoma: a report on 64 cases. 838 56

Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein that contributes to neoplastic cell expansion primarily by promoting cell survival through interference with "programmed cell death" (PCD), also termed "apoptosis." Because many chemotherapeutic drugs are capable of initiating pathways leading to apoptosis, we determined whether deregulated bcl-2 expression could render cells resistant to several drugs commonly used in the treatment of non-Hodgkin's lymphomas, including dexamethasone (DEX), methotrexate (MTX), 1-beta-D-arabinofuranosyl-cytosine (Ara-C), etoposide (VP-16), vincristine (VC), cisplatin (CP), and hydroperoxycyclophosphamide (4-HC). For these experiments, we achieved high levels of p26-Bcl-2 protein production in a human pre-B-cell leukemia line 697 by stable infection with a recombinant bcl-2-containing retrovirus and then compared these cells with control virus-infected 697 cells. Control 697 cells were induced to undergo apoptosis by all drugs tested as defined by DNA degradation into oligonucleosomal-length fragments, cell shrinkage, and subsequent cell death. In contrast, 697 cells with elevated Bcl-2 protein levels exhibited strikingly prolonged cell survival and markedly reduced DNA fragmentation when cultured in the presence of these antineoplastic agents. Although high levels of Bcl-2 protein protected 697 cells from the acute cytotoxic effects of DEX and the other drugs tested, Bcl-2 did not prevent these drugs from suppressing the proliferation of 697 cells. However, when 697 cells were treated with DEX or MTX for 3 days, then washed and cultured in semisolid media without drugs, bcl-2-virus-infected cells gave rise to colonies at much higher frequencies than 697 cells stably infected with control virus. These results indicate that by protecting 697 leukemic cells from the acute cytotoxicity of DEX and some other chemotherapeutic drugs, high levels of p26-Bcl-2 can create the opportunity for re-initiation of cell growth when drugs are withdrawn. The findings may be relevant to clinical correlative studies of non-Hodgkin's lymphoma patients that have found an association between worse prognosis and bcl-2 gene rearrangements or t[14;18] translocations.
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PMID:Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. 841 86

Myeloid leukemias that differ in their competence for induction of differentiation were analyzed for expression of bcl-2 and c-myc and for their sensitivity to induction of apoptosis by heat shock and cancer chemotherapy compounds. The M1 leukemia expressed a high level of bcl-2 and showed a much lower susceptibility to induction of apoptosis by heat shock, Adriamycin, 1-beta-D-arabinofuranosylcytosine, methotrexate, and cycloheximide, compared to five other leukemias which expressed a low level of bcl-2. There was no association between susceptibility to induction of apoptosis and competence for induction of differentiation. The difference in susceptibility to methotrexate, which is not regulated by the multidrug resistance (MDR) genes, and treatment with verapamil, which blocks MDR activity, have indicated that the higher resistance of the M1 leukemia to these agents was not due to MDR activity. The results indicate that the level of regulated bcl-2 expression in these myeloid leukemias was associated with cell susceptibility to induction of apoptosis by different apoptosis-inducing agents. Screening for expression of bcl-2 may thus be useful to characterize leukemias regarding susceptibility to induction of apoptosis by different agents. The level of regulated c-myc expressed in these leukemias was not associated with susceptibility to induction of apoptosis. Transfection with a deregulated mutant p53 into the M1 leukemia did not change susceptibility to apoptosis induction, but transfection with deregulated c-myc increased susceptibility to apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation by bcl-2, c-myc, and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation-competent and -defective myeloid leukemic cells. 842 5


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