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

DNA damage in proliferating mammalian cells induces a complex cellular response comprising perturbation of the cell cycle and programmed cell death. The relationship between p53-dependent and p53-independent apoptotic cell death, as well as the cell cycle checkpoints induced by DNA damaging agents were explored in hematopoietic cells, using M1 myeloblastic leukemia cells, which are null for p53 expression, genetically engineered M1 variants, expressing p53ts and bcl-2 transgenes, as well as myeloblast enriched bone-marrow cells obtained from wild type p53 (wt p53) and p53-deficient mice. It is shown that gamma-irradiation of M1p53ts cells activated a function of the temperature sensitive mutant transgene p53 (p53ts), promoting increased apoptosis relative to parental, null p53 M1 cells. It is also shown that the kinetics of apoptotic cell death induced by gamma-irradiation correlated with the rapidity of exit from gamma-ray-induced G2 arrest for all the different hematopoietic cell types indicated above. Finally, data has been obtained to demonstrate that, in addition to a role in apoptosis and G1 arrest, wild-type p53 positively modulated the exit from the gamma-ray-induced G2 checkpoint. Taken together, these findings indicate that this new function for p53 is a component of the physiological pathway by which p53 exerts its role in apoptosis.
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PMID:p53 involvement in control of G2 exit of the cell cycle: role in DNA damage-induced apoptosis. 778 74

Immunocytochemistry was used to assess bcl-2 expression in blasts obtained from the bone marrow of 28 patients with acute lymphoblastic leukaemia (ALL) (16 children and six adults at presentation and three children and three adults on relapse) and 20 with acute myeloid leukaemia (AML) (19 adults and one child, 13 with de novo AML, 11 at presentation and two on relapse, and seven secondary to myelodysplasia or chronic myeloid leukaemia). Slides were examined both for the percentage of positive cells and for the intensity of staining using a five-point scale. There was a statistically significant increase in both the percentage of positive cells seen (P < 0.002) and the intensity of staining (P < 0.01) between samples obtained at relapse and those at presentation in ALL. There was a significantly greater intensity of staining in cells from patients with ALL (P < 0.05) and AML (P < 0.05) who failed to achieve remission after chemotherapy than in those who responded. The intensity of staining in cases of secondary AML was lower than that in de novo disease (P < 0.01). These results suggest that expression of bcl-2 may be an important prognostic feature in both de novo AML and in ALL, but not in secondary AML.
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PMID:The relationship between bcl-2 expression and response to chemotherapy in acute leukaemia. 780 31

The cancer chemopreventive retinoid N-(4-hydroxyphenyl)-all-trans retinamide (HPR) was recently shown by us to have antiproliferative and apoptotic effects on human leukemic cell lines, including those unresponsive to all-trans retinoic acid (ATRA). We have now characterized further the process of HPR-induced cell death. We report that inhibitors of RNA transcription and of protein synthesis, activators of protein kinase C (PKC), inhibitors of tyrosine kinases, Zn++, and the antioxidants acetylcysteine, ascorbic acid, alpha-tocopherol, and deferoxamine suppressed HPR-induced apoptosis. HL60 cells induced toward monocytic differentiation by 1,25 dihydroxyvitamin-D3 [1,25(OH)2D3], but not those induced toward the granulocytic differentiation by ATRA, showed reduced responses to HPR. The transport of HPR by cells with different sensitivity to the retinoid, however, was similar, even after treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), which induces unresponsiveness to HPR. The expression of the apoptosis-related genes bcl-2, p53, and c-myc was examined to determine their role in HPR-triggered cell death. The levels of bcl-2 mRNA were markedly diminished by 24 hours of HPR treatment in all cell lines except in the relatively HPR-insensitive line K422. However, probably because of its long half-life, bcl-2 protein levels were either unchanged or only slightly decreased. Downregulation of p53 mRNA was also observed within 24 hours of HPR exposure in NB4 but not K422 cells, but no changes in the amount of p53 protein were found. Suppression of c-myc transcription was observed in all cells except K422. The protective role of bcl-2 on cell death by HPR was investigated in HL60 as well as 697 pre-B leukemia and Jurkat T-acute lymphocytic leukemia (T-ALL) cells constitutively expressing high levels of bcl-2 proteins due to gene transfer manipulation. Compared with control cells, the onset of apoptosis in these cells with deregulated bcl-2 production was delayed by at least 24 hours. These findings establish that cell death by HPR requires RNA transcription and protein synthesis and is regulated by the activation of PKC. Although changes in bcl-2, p53, and c-myc expression are found in cells treated with HPR, the time-course of these events suggests that HPR-triggered apoptosis is not directly controlled by these genes. Finally, while ectopic overexpression of bcl-2 does not protect cells from death by HPR, it markedly delays its onset.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2. 781 93

We have previously shown that blasts from acute myeloid leukaemia (AML) patients which grow autonomously in culture have high bcl-2 expression which in turn has been linked to a poor clinical response to chemotherapy. The bcl-2 protein promotes cell survival by preventing the onset of apoptosis or programmed cell death following growth-factor deprivation. Bcl-2 has also been shown to be responsible for chemo-resistance in human leukaemic cell lines. Here we have investigated the role of bcl-2 expression in mediating resistance to apoptosis induced by cytosine arabinoside in vitro. The blasts from 17 AML patients exhibiting autonomous growth in a blast cell colony assay and expressing high levels of bcl-2 protein were studied. Incubation of the blasts with antisense oligonucleotides directed against bcl-2 mRNA resulted in a significant decrease in expression of the bcl-2 protein in seven of the 17 samples. In these seven cases the decreased expression of bcl-2 was accompanied by increased apoptosis and the susceptibility of the blasts to apoptosis induced by Ara-C was increased in the presence of bcl-2 antisense. As a high level of bcl-2 defines a group of AML patients who exhibit a poor response to chemotherapy, the demonstration that chemosensitivity of a significant proportion of these patients can be increased by bcl-2 antisense suggests this approach may have clinical potential.
Leukemia 1995 Jan
PMID:Inhibition of bcl-2 with antisense oligonucleotides induces apoptosis and increases the sensitivity of AML blasts to Ara-C. 784 7

Morphologically HL-60 leukaemia cells largely resemble promyelocytes and can be induced to terminally differentiate in vitro. Upon reaching terminal maturation these cells rapidly undergo apoptosis. Using three chemotherapeutic agents with known apoptosis inducing capability, the susceptibility of RA - and PMA - differentiated cultures was monitored by morphological means and flow cytometry. We observed that as cells with morphological characteristics of mature granulocytes/monocytes became more prominent in the populations, there was an increased resistance to apoptosis. The inhibition of the typical internucleosomal DNA fragmentation was confirmed by agarose gel electrophoresis. However, activation of a CA+/Mg+ independent endonuclease in isolated nuclei was not affected. Flow immunocytometry revealed reduced levels of c-myc and bcl-2 oncoproteins in RA and PMA treated cells. These observations suggest that HL-60 derived granulocytes/monocytes become increasingly resistant to the induction of apoptosis and that this resistance is independent of c-myc and bcl-2 expression. Together these results demonstrate that the phenotypic changes associated with RA and PMA induced differentiation, inhibit a critical step in the progression of apoptosis.
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PMID:Increased resistance to apoptosis associated with HL-60 myeloid differentiation status. 784 52

A family of genes related to the bcl-2 protooncogene has recently emerged. One member of this family, mcl-1, was cloned from a human myeloblastic leukemia cell line (ML-1) undergoing differentiation. The intracellular localization of mcl-1, as well as the kinetics of its expression during differentiation, have now been studied. These studies show that the intracellular distribution of mcl-1 overlaps with, but is not identical to, that of bcl-2: mcl-1 is similar to bcl-2 in that the mcl-1 protein has a prominent mitochondrial localization, and in that it associates with membranes through its carboxyl hydrophobic tail. mcl-1 differs from bcl-2, however, in its relative distribution among other (nonmitochondrial/heavy membrane) compartments, mcl-1 also being abundant in the light membrane fraction of immature ML-1 cells while bcl-2 is abundant in the nuclear fraction. Similarly, in differentiating ML-1 cells, the timing of expression of mcl-1 overlaps with, but is not identical to, that of bcl-2: the mcl-1 protein increases rapidly as cells initiate differentiation, and mcl-1 is a labile protein. In contrast, bcl-2 decreases gradually as cells complete differentiation. Overall, the mcl-1 and bcl-2 proteins have some properties in common and others tht are distinct. A burst of expression of mcl-1, prominently associated with mitochondria, complements the continued expression of bcl-2 in ML-1 cells differentiating along the monocyte/macrophage pathway.
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PMID:The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2. 789 80

Taxol-resistant sublines of HL-60 myeloid leukemia cells (HL-60/TAX100 and HL-60/TAX1000) have been isolated in vitro by subculturing in progressively higher concentrations of taxol. HL-60/TAX100 and HL-60/TAX1000 cells are capable of continuous growth in the presence of 0.1 microM and 1.0 microM taxol, respectively, and the IC50 (50% growth inhibitory dose) values for taxol for the two sublines are 0.34 and 2.44 microM as compared to 3.1 nM for the parent HL-60 cells. HL-60/TAX100 and HL-60/TAX1000 cells display a variable degree of cross-resistance to taxotere, vincristine and doxorubicin, but are sensitive to the antimetabolite Ara-C. Both HL-60/TAX100 and HL-60/TAX1000 cells over-express MDR-1 m-RNA and the membrane efflux multidrug transporter P-glycoprotein (PGP), as determined by Western blot and immunofluorescence labeling with anti-PGP antibodies. Consequently, exposure of the taxol-resistant cells to [3H]taxol or daunomycin results in the accumulation of significantly lower levels of the two drugs. Co-treatment with cyclosporine (0.5 microgram/ml) or verapamil (10 microM) partially overcomes taxol resistance in HL-60/TAX1000 cells. Following treatment with clinically relevant concentration of taxol (1.0 microM for 24 h), HL-60 but not HL-60/TAX1000 cells display intracellular microtubular bundling, markedly enhanced accumulation of the cells in G2/M phase of cell-cycle and internucleosomal DNA fragmentation associated with apoptosis which is independent of bcl-2 gene expression. These taxol-resistant myeloid leukemia cells may serve as in vitro experimental models for examinating strategies which may have potential applicability for overcoming taxol resistance.
Leukemia 1994 Mar
PMID:Characterization of a human myeloid leukemia cell line highly resistant to taxol. 790 95

In order to thoroughly characterize the clonal population of lymphoid hyperplasia of the orbit and conjunctiva, we investigated six cases which were histologically proven to be benign lymphoid hyperplasia. We analyzed the clonal rearrangements of the antigen receptors and bcl-2 gene, Epstein-Barr virus (EBV), and human T-cell leukemia virus type 1 (HTLV-I) by Southern blot and/or polymerase chain reaction (PCR), and performed in situ hybridization for mRNA of kappa and lambda immunoglobulin. Five cases showed rearrangements of immunoglobulin heavy chain gene (JH) and/or light chain gene (J kappa), and the monoclonal V-J recombination of JH in PCR. However, the rearranged bands were much more faint than was the germ-line band. We considered the monoclonal population of B cells small. Two of the five cases recurred locally after four and nine years respectively. Because benign lymphoid hyperplasias frequently contain an occult monoclonal B-cell population, a follow-up should be conducted. The remaining case in our investigation showed a rearrangement of the T-cell-receptor gene and proviral DNA of HTLV-I, and it showed rapid progress to adult T-cell leukemia after the biopsy. EBV and bcl-2 gene rearrangements were not observed in any of the six cases we studied.
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PMID:Clonality of benign lymphoid hyperplasia in orbit and conjunctiva. 799 65

A phenotypic and molecular evaluation was made of 15 patients with mature B-cell leukemia/lymphoma showing exclusive spleen and bone marrow involvement. According to French-American-British criteria, these cases could not be classified as classical B-cell chronic lymphocytic leukemia, hairy cell leukemia and its variant forms, splenic lymphoma with villous lymphocytes, or leukemic phase non-Hodgkin's lymphoma (NHL; follicular or intermediate type). The immunophenotype pattern (high surface Ig and CD25 expression, and little or no reactivity with CD5, CD23, and CD11c) and cytomorphologic features of these neoplasms suggested an origin in the marginal zone of the spleen. Molecular analysis did not show any involvement of the dominantly acting oncogenes generally associated with lymphoid malignancies (c-myc, bcl-2, bcl-1, Ras), but mutations of the p53 tumor suppressor gene involving exons 5, 6, and 8 were found in 6 cases (6 of 15, 40%). In 4 cases, the p53 alterations consisted of a point mutation leading to amino acid substitution. In the remaining 2 cases, an insertion or deletion resulting in a frame-shift of the protein was observed. In all but 1 of the cases, the wild-type sequence at the mutation site was barely visible, implying the loss of the normal p53 allele in leukemic cells. All of the cases showed a clinical course compatible with that of low-grade NHL, regardless of the p53 loss/mutation. Overall, our data suggest the existence of a form of splenic B-cell leukemia/lymphoma of possible marginal zone origin in which p53 inactivation may play an important pathogenetic role.
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PMID:Frequent p53 gene involvement in splenic B-cell leukemia/lymphomas of possible marginal zone origin. 801 22

A polymerase chain reaction analysis of biopsy specimens from a total of 52 patients with Hodgkin's disease has revealed the presence of the t(14;18) chromosomal translocation in 14 cases (28%). Twelve involved the major breakpoint region and two included the minor cluster region of the bcl-2 gene. Direct sequencing of the amplified 14q+ junctions from the initial four positive cases (from 21 biopsies) has been previously published and demonstrated the similarity in nature of the break-points to those described in follicular lymphoma and lymphoid hyperplasia. The 52 biopsies have also been studied with a monoclonal antibody to immunolocalize the Bcl-2 protein. In all cases Bcl-2 positivity was observed in the majority of surrounding lymphocytes. However, in 11 cases, positive immunostaining in the Sternberg-Reed cells was also observed. Three of these cases contained the t(14;18) translocation, but 11 cases which were positive for the t(14;18) by PCR did not show Bcl-2 protein staining in the Sternberg-Reed cells. This data confirms the presence of t(14;18) in 28% of biopsies from Hodgkin's disease and demonstrates Bcl-2 protein staining in a variable proportion of Sternberg-Reed cells of some cases.
Leukemia 1994 Aug
PMID:The t(14;18) chromosomal translocation and Bcl-2 protein expression in Hodgkin's disease. 805 70


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