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

Human T-cell leukemia virus type I (HTLV-I) is an etiological agent of adult T-cell leukemia. The Tax protein of HTLV-I may play a central role in cellular transformation. By serum deprivation, Tax-transformed Rat-1 cells undergo apoptotic cell death. These cells exhibit DNA fragmentation and chromatin condensation. Constitutive expression of bcl-2, blocked Tax-mediated apoptosis. Activation of fusion protein containing Tax and estrogen receptor, also led to the trans-activation and caused inhibition of proliferation and apoptosis. However Tax inhibited anti-Apo-1-induced apoptosis. Apoptosis appear to be the most important process of HTLV-I associated myelopathy (HAM). In spinal cords from autopsied patients with HAM/TSP, apoptosis of helper-inducer T lymphocytes was observed. HTLV-I carrier WKAH rats developed myeloneuropathy and apoptotic death of oligodendrocytes. The apoptosis was consistent with HTLV-I pX expression.
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PMID:[The human T-cell leukemia virus type I (HTLV-I) tax protein induces apoptosis]. 874 78

Apoptosis plays a critical role during T cell development, both in the generation of functionally competent T cells in the thymus and the regulation of peripheral T cell populations. The fate of any T cell, whether it is developing in the thymus, or functioning in the peripheral immune system, is dependent on T cell receptor (TCR) specificity for antigens presented by MHC molecules and on the consequences of TCR-generated intracellular signalling pathways which lead to activation, anergy or apoptosis. This review describes data that have elucidated the way in which these highly regulated TCR-derived signalling pathways lead to such diverse final outcomes in thymocytes. Contributions to the induction of apoptosis in thymocytes by signalling pathways and receptors such as Fas, CD45 and CD28 are summarized, particularly with regard to the analysis of relevant transgenic mice. Developments concerning regulation of apoptosis by bcl-2 family members and the possible effectors of apoptosis, proteases, are assessed. Finally, this information is contrasted with the relatively scarce data on signalling pathways in thymic-derived T-ALL cells together with potential explanations of how transformation might occur by perturbation of apoptotic mechanisms. Precise understanding of these pathways may lead to the development of novel therapeutic reagents.
Leukemia 1996 Sep
PMID:The role of intracellular signalling pathways regulating thymocyte and leukemic T cell apoptosis. 875 58

All-trans retinoic acid (RA) is the first highly effective differentiation-inducing agent for remission induction in patients with acute promyelocytic leukemia. However, remissions are short-lived because the treatment fails to induce complete differentiation and fails to eradicate the malignant clone. To eliminate rapidly the malignant clone, in analogy with aggressive chemotherapy, the combination of potent differentiation- and apoptosis-inducing drugs working through different receptors and signal pathways may be useful. The active form of vitamin D3 (1,25-dihydroxyvitamin D3; 1,25(OH)2D3) inhibits proliferation and induces differentiation of myeloid leukemic cells. The 9-cis-RA, unlike all-trans-RA which binds only retinoic acid receptors, is a high affinity ligand for both retinoic acid receptors and retinoid X receptors. The aim of this study was to evaluate the therapeutic potential of combining a vitamin D(3) analogue, 20-epi-22-oxa-24a,26a,27a-tri-homo-1alpha,25(OH) 2D, (KH 1060), which belongs to the family of potent 20-epi-1,25(OH),D3 analogues, with 9-cis-RA by assessing their effects on the proliferation, differentiation, and apoptosis of the human leukemia cell line HL-60 in vitro. Our data show that KH 1060 alone is a very potent inhibitor of clonal proliferation of HL-60, but this effect is reversible, and that 9-cis-RA alone is a weak inhibitor of clonal proliferation of HL-60 cells. In contrast, the combination of KH 1060 and 9-cis-RA synergistically and irreversibly inhibited the clonal proliferation of HL-60 cells and induced apoptosis, as detected by morphological changes and DNA fragmentation. This combination also affected the expression of apoptosis-related genes. The bcl-2 protein became nearly undetectable, and expression of bax protein increased slightly (the bax:bcl-2 ratio was 14-fold higher than in untreated cells). Differentiation of treated HL-60 cells was assessed by their ability to produce superoxide, as measured by reduction of nitro blue tetrazolium, positive staining for alpha-naphthyl acetate esterase, phagocytosis, morphology, and analysis of membrane-bound differentiation markers with two-color immunofluorescence. Treatment with the combination of KH 1060 and 9-cis-RA was a potent inducer of differentiation of HL-60, with the cells developing a myelomonocytic phenotype. In summary, our data demonstrate that the combination of both KH 1060 and 9-cis-RA irreversibly and synergistically inhibited clonal growth, induced differentiation and apoptosis of HL-60 cells concomitantly with a very marked decreased expression of bcl-2, and increased the bax:bcl-2 ratio. This drug combination may have important therapeutic significance.
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PMID:Combination of a potent 20-epi-vitamin D3 analogue (KH 1060) with 9-cis-retinoic acid irreversibly inhibits clonal growth, decreases bcl-2 expression, and induces apoptosis in HL-60 leukemic cells. 875 28

Mice deficient for B cell leukemia/lymphoma gene 2 [bcl-2(-/-) mice] manifest congenital renal hypoplasia and develop multicystic kidney disease and renal failure postnatally. To characterize postpartum renal development, to identify the cellular origin of the cysts, and to provide insight into the role that bcl-2 deficiency plays in the cystogenic process, we examined the morphology of kidneys from bcl-2 (-/-) mice and wild-type littermates [bcl-2 (+/+)] from birth (P0) to postpartum day 28 (P28), determined whether abnormalities of cellular proliferation and apoptosis accompany cyst development, and characterized expression of the bcl-2-related protein, bax. Between P0 and P7, kidneys from bcl-2 (-/-) and bcl-2 (+/+) mice undergo a comparable increase in weight and have similar histological appearances. However, during the next 2 wk of life, weight gain in kidneys from bcl-2 (-/-) mice is reduced compared with that in kidneys from bcl-2 (+/+) animals, and cysts develop in tubules with staining characteristics of proximal tubule, distal tubule/medullary thick ascending limb of Henle's loop, and collecting duct. Unaffected glomeruli and proximal tubules in kidneys of bcl-2 (-/-) mice undergo compensatory growth. Cystogenesis is accompanied by enhanced incorporation of 5-bromo-2'-deoxyuridine in cells within cortex and medulla and apoptosis of cells within cysts and in the renal interstitium. Bax protein is expressed in the distal tubule in kidneys of bcl-2 (+/+) and bcl-2 (-/-) mice and in some, but not all cysts. We conclude that abnormal regulation of DNA synthesis and apoptosis accompany cystogenesis in bcl-2 (-/-) mice during postpartum kidney development. Continued expression of bax could enhance apoptotic cell death.
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PMID:Abnormal postpartum renal development and cystogenesis in the bcl-2 (-/-) mouse. 876 Feb 59

The Fas/Apo-1 molecule is a member of tumor necrosis factor/nerve growth factor (TNF/NGF) receptor family and is able to induce apoptosis in various type of malignant cells, including most of the human leukemia T-cells. We previously demonstrated that the Fas-resistant variants may exist in highly Fas-sensitive human leukemia T-cell lines. The surface expression of Fas antigen was unchanged in the variant cells, suggesting the requirement of the cytoplasmic mechanism to exert apoptosis. In the present study, we examined the changes in cytoplasmic proteins of the Fas-sensitive and Fas-resistant cells after stimulation with anti-Fas antibody, 2D1. In Western blotting analysis, we found that the stimulation of Fas-sensitive cells with 2D1, but not resistant variants, induced a repression of cyclin-dependent kinases (cdks), p34cdc2 and p33cdk2, along with apoptosis. There was no alteration in the expression of bcl-2, HSP70, HSP90, and cyclin proteins examined. This observation seemed specific to Fas-mediated apoptosis, because calcium ionophore A23187 or sodium azide failed to repress the expression of cdks. These results indicate that the specific depletion of cdks, most likely due to proteolysis, may play a role in Fas-mediated apoptosis.
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PMID:Selective depletion of cyclin-dependent kinases is associated with Fas-mediated apoptosis in human leukemia T-cell lines. 878 21

High levels of expression of the bcl-2 oncoprotein in acute myeloblastic leukaemia (AML) cells have been associated with low complete remission rates and poor survival. The sensitivity of AML blasts to drugs such as Ara-C can be increased by the down-regulation of bcl-2 expression by antisense oligonucleotides. All-trans retinoic acid (ATRA) has been reported to increase the sensitivity of AML cell lines to Ara-C and to induce differentiation in the HL60 promyelocytic cell line, with both effects being accompanied by a decrease in bcl-2 expression. Using flow cytometry and a monoclonal antibody to bcl-2, we have investigated the effects of ATRA (1 microM) on bcl-2 expression in the blast cells of 25 AML patients and the K562 cell line after incubation for 72 or 24 h, respectively. Using Kolmogorov-Smirnov statistical analysis where a D value of > 0.12 was statistically significant, we found that in 8/25 AML samples and the K562 cells there was a significant decrease in bcl-2 protein expression after incubation with ATRA (D value range 0.14-0.44). The mean peak fluorescence (MPF) values for the bcl-2 levels of the ATRA responders (n = 8) was reduced to 35.5 +/- 6.9 following incubation with ATRA compared to 47.6 +/- 8.2 (mean +/- SEM) for control samples incubated in the absence of ATRA (P = 0.014). There was no significant difference between the baseline bcl-2 molecules of equivalent soluble fluorochrome (MESF) levels in the ATRA responders (48.9 +/- 5.7, n = 8) and the non-responders (41.3 +/- 3.9, n = 17) (mean +/- SEM) (P = 0.28). The down-regulation of bcl-2 expression by ATRA was particularly associated with CD34-negative AML and of the eight AML patients' cells that responded to ATRA by down-regulating bcl-2, seven were CD34 negative (P < 0.05). Our data suggest that the addition of ATRA to combination chemotherapy would increase the chemosensitivity of some patients with AML, particularly CD34-negative AML, due to down-regulation of bcl-2 expression.
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PMID:Down-regulation of bcl-2 in AML blasts by all-trans retinoic acid and its relationship to CD34 antigen expression. 882 91

The bcl-2 protein suppresses apoptosis and the bax protein opposes the cytoprotective effect of bcl-2. A decrease in bcl-2 levels has been implicated in the induction of apoptosis during the terminal differentiation of HL60 myeloid leukaemia cells. We show here that bax protein also declined with a time course similar to the downregulation of bcl-2 following treatment of HL60 with phorbol myristate acetate (PMA), dimethyl sulphoxide (DMSO) or retinoic acid (RA). Decreased bcl-2 protein expression in induced cells was associated with down-regulation of its mRNA. By contrast, the decrease in bax occurred by a post-transcriptional mechanism. Co-ordinate downregulation of bcl-2 and bax proteins may fine-tune the induction of apoptosis during cellular differentiation.
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PMID:Co-ordinated downregulation of bcl-2 and bax expression during granulocytic and macrophage-like differentiation of the HL60 promyelocytic leukaemia cell line. 883 Jun 74

An Epstein-Barr virus (EBV)-negative Burkitt's lymphoma (BL) cell line, designated Black93, was established in culture from a patient who developed acute tumor lysis syndrome (ATLS). Growth inhibition in vitro by dexamethasone (DXM) and the expression of bcl-2 protein (Bcl-2) were investigated in Black93 and 17 other cell lines derived from EBV-negative or -positive BL, pre-B acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), and EBV-positive lymphoblastoid cell lines of normal B cell origin (B-LCL), assuming an inherent susceptibility of Black93 to cell death. The most marked growth inhibition by DXM was observed in Black93, two other BL, two pre-B-ALL and two FL lines. The other cell lines were less sensitive or were resistant. DNA extracted from the Black93 cells treated with DXM showed a ladder of oligo-nucleosomal DNA on electrophoresis. On testing of fixed smears by indirect immunofluorescence, bcl-2 protein (Bcl-2) was undetectable in Black93 and three BL lines but was detected in all the other cell lines at varying intensity. Western blot analysis showed mostly the same results. In the BL lines, the most DXM-sensitive cell lines lacked Bcl-2 expression, and the DXM-resistant cell lines always expressed Bcl-2. While none of the DXM-resistant cell lines lacked Bcl-2 expression, several pre-B or FL lines that expressed [correction of expessed] Bcl-2 were sensitive to DXM. Black93 is the first reported cell line established from a patient with ATLS. The positive sensitivity to DXM and the lack of Bcl-2 expression observed in Black93 are a major characteristic exhibited frequently by BL lines and, probably, by fresh BL cells. These properties may contribute to the precipitation of ATLS.
Leukemia 1996 Oct
PMID:Sensitivity to dexamethasone and absence of bcl-2 protein in Burkitt's lymphoma cell line (Black93) derived from a patient with acute tumor lysis syndrome: comparative study with other BL and non-BL lines. 884 94

Sunburn cells (SBCs) appear in the epidermis shortly after acute UV damage, especially after exposure to UVB light. As yet, the mode of their formation remains to be satisfactorily elucidated. In order to characterize these cells, the expression of various markers of epidermal differentiation following UV exposure was investigated using immunhistochemical procedures. These were applied to paraffin-embedded (microwave technique) and frozen specimens of human skin 24 h after irradiation with 4 times the minimal erythema doses(MED). Normal nonirradiated skin without irradiation served as the control. We used a battery of antibodies directed against the following: cytokeratins (CKs) 5, 10, 17, and 19, actin, cell-adhesion proteins (desmoplakins, desmogleins), markers of terminal epidermal differentiation (filaggrin, involucrin and loricrin), markers of proliferation (PCNA, MIB, K6,16), a marker of endocytosis (clathrin) and markers of cell growth, (transforming growth factor [TGF-alpha]) and B-cell leukemia/lymphoma-2 [bcl-2]. After UV irradiation it was found that CK 5, which is typically confined to basal keratinocytes, was also expressed in suprabasal keratinocytes. The CKs 1 and 10/11 exhibit a normal suprabasal localization, but suprisingly, SBCs were negative for these CKs. Although CK 6,16, and 17 are not usually found in normal epidermis, UVB exposure induced their expression in suprabasal keratinocytes, but again failed to elicit their expression in SBCs. Antibodies specific for markers of late epidermal differentiation (filaggrin, involucrin and loricrin), cell-junction proteins (desmogleins, desmoplakins), proliferation (PCNA and MIB), and endocytosis (clathrin) also failed to produce positive staining of SBCs. Even though TGF-alpha immunoreactivity became detectable in most keratinocytes after UV exposure, this was not the case for SBCs. The number of basally located dendritic cells, most probably melanocytes, exhibiting bcl-2 staining was markedly reduced 6 and 12 h after irradiation as compared with normal skin. SBCs do not express any late differentiation markers, but they do contain proteins typical of basal keratinocytes (CK 5). It can be concluded that SBCs do not develop beyond a more basal-like differentiation pattern, probably as a result of cell death and migration through the epidermis.
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PMID:Characterization of sunburn cells after exposure to ultraviolet light. 885 Feb 47

We examined the effects of high intracellular levels of Bcl-2 on the metabolism and DNA incorporation of high-dose Ara-C (HIDAC) as well as on Ara-C-induced DNA strand breaks and apoptosis of human AML HL-60 cells. HL-60/Bcl-2 and HL-60/neo cells were created by retrovirally transfecting the human AML HL-60 cells with the pZip-bcl-2 and pZip-neo plasmids, respectively. As compared to HL-60/neo, HL-60/Bcl-2 cells contained significantly higher (approximately 10-fold) p26Bcl-2, but equivalent levels of Bax and undetectable levels of Bcl-xL. HIDAC (10 or 100 microM for 4 h) produced the kilobase size and internucleosomal DNA fragmentation associated with apoptosis in HL-60/neo but not in HL-60/Bcl-2 cells. Significantly greater loss of survival (by MTT assay) and flowcytometric and morphologically recognizable apoptosis were observed in HL-60/neo cells. HIDAC did not affect Bcl-2 levels in either cell type. The intracellular accumulation of Ara-CTP relative to dCTP, Ara-C DNA incorporation and Ara-C-induced early DNA damage in the form of strand breaks (detected by alkaline elution assay) were not significantly different between HL-60/Bcl-2 and HL-60/neo cells. In addition, HIDAC treatment caused similar DNA synthesis inhibition in the two cell types. These results indicate that high intracellular levels of Bcl-2 operate distally to inhibit the final apototic cell death pathway by preventing the conversion of HIDAC-induced early DNA damage into lethal DNA fragmentation associated with apoptosis.
Leukemia 1996 Nov
PMID:Intracellular metabolism of Ara-C and resulting DNA fragmentation and apoptosis of human AML HL-60 cells possessing disparate levels of Bcl-2 protein. 889 76


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