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

The chromosomal translocation involving 3q27 has been recently described in B-cell malignancies, especially in diffuse large cell lymphomas. We have previously cloned the breakpoint cluster region of 3q27 designated as the BCL6 locus, previously known as BCL5, and subsequently cloned the cDNA for the BCL6 (we previously reported it as BCL5) gene encoding a novel Cys2-His2 zinc-finger protein, which locates adjacent to the breakpoints and is activated through the translocation. To elucidate whether rearrangements occur within the BCL6 gene, we characterized the genomic structure of the gene. The BCL6 gene encompasses about 26 kilobases (kb) and consists of nine exons. Translation start site is located in exon 3 and zinc-finger motif is distributed in the exons 6 to 9. We have identified at least two types of mRNA alternatively spliced, which contain or do not contain exon 2 of 134 bp coding for the 5' untranslated region. A large intron 1 of 9 kb is not efficiently spliced out, which might result in the creation of minor 10-12-kb transcripts observed in the Northern blot analysis in addition to major 3.8-kb transcripts. The breakpoints are clustered around the first exon, and the putative regulatory region of the BCL6 gene is removed through the translocation, leading to the over-expression of the gene.
Leukemia 1994 Aug
PMID:The organization of the BCL6 gene. 805 68

Rearrangements involving chromosome band 11q23 are very common in acute leukaemia, both lymphoblastic and myeloid (monoblastic), and are less common in lymphoma. Although several different genes have been cloned from translocation breakpoints, the great majority of translocations involve the MLL (myeloid-lymphoid leukaemia) gene. The MLL gene has several different names, ALL1, Htrx, HRX; the central part of the gene codes for multiple zinc fingers which show strong homology to the Drosophila trithorax gene. MLL is involved in four common translocations as well as in 25 uncommon or rare translocations, insertions and deletions. The translocation breakpoints occur within an 8.3 kb region which can be detected with a 0.74 kb cDNA probe. Twenty-five percent of patients have a deletion 3' of the breakpoint which includes the zinc finger region. Patients who previously received drugs that inhibit topoisomerase II often develop acute leukaemia with translocations involving 11q23. These translocations break MLL in the same 8.3 kb region. In the three breakpoints cloned to date, the translocation has led to a fusion gene on the derivative 11 chromosome with a chimaeric transcript, consisting of 5' MLL and the 3' segment of the other gene. Although transcripts were also cloned from the other derivative chromosome, all the evidence indicates that the critical fusion gene is on the derivative 11 chromosome. The molecular dissection of these rearrangements will provide insights into the biology of MLL and into the interaction of MLL with topoisomerase II inhibitors. In addition, this research has provided DNA probes that will be important for diagnosis and for monitoring patients during the course of their disease.
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PMID:Rearrangements involving chromosome band 11Q23 in acute leukaemia. 814 23

Rearrangements involving chromosome band 11q23 are very common in acute leukemia, both lymphoblastic and myeloid (monoblastic), and are less common in lymphoma. Although several different genes have been cloned from 11q23 translocation breakpoints, the great majority involve the MLL (myeloid-lymphoid leukemia) gene. The MLL gene has several different names, ALL1, Htrx, HRX; the central part of the gene codes for multiple zinc fingers which show strong homology to the Drosophila trithorax gene. MLL is involved in four common translocations as well as in 25 uncommon or rare translocations, insertions and deletions. The translocation breakpoints occur within an 8.3kb region which can be detected with a 0.7 kb cDNA probe. Twenty-five percent of patients have a deletion 3' of the breakpoint which includes the zinc finger region. Patients who previously received drugs that inhibit topoisomerase II often develop acute leukemia with translocations involving 11q23. These translocations break MLL in the same 8.3kb region. In the four breakpoints cloned to date, the translocation has led to a fusion gene on the derivative 11 chromosome with a chimeric transcript, consisting of 5' MLL and the 3' segment of the other gene. Although transcripts were also cloned from the other derivative chromosome, all the evidence indicates that the critical fusion gene is on the derivative 11 chromosome. The molecular dissection of these rearrangements will provide insights into the biology of MLL and into the interaction of MLL with topoisomerase II inhibitors. In addition, this research has provided DNA probes that will be important for diagnosis and for monitoring patients during the course of their disease.
Leukemia 1994 Apr
PMID:1993 Robert R. deVilliers Lecture. Chromosome translocations: dangerous liaisons. 815 72

The involvement of zinc ions in cell metabolic processes and the immunopathologic consequences of zinc deficiency are well known. We investigated the effect of zinc aspartate upon production of reactive oxygen species (ROS) by monocytes and polymorphonuclear cells isolated from healthy subjects and patients with leukemia and rheumatoid arthritis. The cells were stimulated in vitro with serum-treated zymosan, aggregated IgG, aggregated and opsonized IgG and digitonin. Zinc concentrations of 10(-4)M do not influence the in vitro release of ROS by polymorphonuclears but moderately activate the monocytes. Following treatment with orally administered zinc aspartate, monocytes from leukemia patients reveal an increased capacity to release ROS after in vitro stimulation. In patients with rheumatoid arthritis monocytes usually produce abnormally high ROS amounts after in vitro stimulation; the treatment with zinc aspartate does not induce considerable alterations of this capacity; however a tendency to restore the normal values is manifest.
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PMID:Zinc aspartate in vivo and in vitro modulation of reactive oxygen species production by human neutrophils and monocytes. 818 53

Leukotriene A4 hydrolase is a bifunctional metalloenzyme that contains 1 mol of zinc per mole of protein. The primary function of the metal is catalytic and zinc is thus necessary for both its peptidase and its epoxide hydrolase activity. However, at concentrations of zinc exceeding a 1:1 molar ratio (metal:enzyme), we found that zinc acted as an inhibitor with IC50 values of 10 microM for the epoxide hydrolase activity, i.e., the conversion of leukotriene A4 to leukotriene B4, and 0.1 microM for the peptidase activity. The inhibition of both enzyme activities could be reversed by treating the enzyme with chelating agents such as EDTA or dipicolinic acid. Several divalent cations, other than zinc, were also found to inhibit leukotriene A4 hydrolase although with different specificity and potency for the two enzyme activities. Thus, CdSO4 and HgCl2 were effective inhibitors (IC50 approximately 10 microM) of the epoxide hydrolase activity, whereas CoCl2 or MnCl2 were not inhibitory even at concentrations of 1 mM. On the other hand, the peptidase activity was inhibited by CdSO4, NiSO4, HgCl2, MnCl2, CoCl2, and PbNO3, listed in decreasing order of potencies (IC50 0.5-10 microM). In addition, zinc in micromolar concentrations inhibited leukotriene B4 formation in intact human polymorphonuclear leukocytes stimulated by the calcium ionophore A23187 and cell homogenates incubated with arachidonic acid. However, this effect was not related to inhibition of leukotriene A4 hydrolase but rather to a direct or indirect inhibitory effect on the enzyme 5-lipoxygenase in isolated leukocytes. In these cells, 15-lipoxygenase activity was also inhibited by zinc (IC50 5 microM), whereas leukotriene C4 synthase activity in human platelets and rat basophilic leukemia cells was significantly affected only at concentrations > or = 1 mM.
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PMID:Zinc and other divalent cations inhibit purified leukotriene A4 hydrolase and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes. 820 89

The murine B-lymphocyte differentiation antigen BP-1/6C3 has been identified as glutamyl aminopeptidase (E-AP), formerly known as aminopeptidase A, the new gene symbol for which is ENPEP. In mice, the enzyme is found on early B-lineage cells and certain stromal cells of the bone marrow and thymus. This ectopeptidase is also expressed by capillary endothelial cells, placenta, and epithelial cells of the intestine and proximal renal tubules. Here we have used a mouse E-AP cDNA to identify the human counterpart in a kidney library. Sequence comparison of the human and mouse cDNAs reveals approximately 80% homology at both nucleotide and predicted amino acid levels. The nucleotide sequence of human E-AP predicts a type II integral membrane protein of 957 amino acids with an 18-amino-acid aminoterminal intracellular domain, and a 22-amino-acid transmembrane domain. The large extracellular carboxyterminal domain contains the zinc-binding motif typical of zinc-dependent metallohydrolases. When the human E-AP cDNA was placed downstream of the SR alpha promoter in an expression vector and transfected into COS-7 cells, the transfected cells exhibited cell surface E-AP activity. A 4.1-kb transcript could be detected in a variety of human tissues, including heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas. However, in representative lymphoid leukemias, E-AP transcripts were restricted to pre-B leukemia and were not found in T- and B-cell leukemias. The cDNA cloning and successful expression of human E-AP will allow more precise analysis of its physiological role(s).
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PMID:cDNA cloning and expression of human glutamyl aminopeptidase (aminopeptidase A). 824 82

Zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)-acetic acid], a membrane-permeant fluorophore specific for Zn(II), was used with spectrofluorimetry and video image analysis to reveal and quantify labile intracellular Zn. Zinquin labelled human chronic-lymphocytic-leukaemia lymphocytes, rat splenocytes and thymocytes with a weak diffuse fluorescence that was quenched when intracellular Zn was chelated with NNN'N'-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and was greatly intensified by pretreatment of cells with the Zn ionophore pyrithione and exogenous Zn. There was substantial heterogeneity of labile Zn among ionophore-treated cells, and fluorescence was largely extranuclear. The average contents of labile Zn in human leukaemic lymphocytes, rat splenocytes and rat thymocytes were approx. 20, 31 and 14 pmol/10(6) cells respectively. Morphological changes and internucleosomal DNA fragmentation indicated substantial apoptosis in these cells when the level of intracellular labile Zn was decreased by treatment with TPEN. Conversely, increasing labile Zn by pretreatment with Zn plus pyrithione suppressed both spontaneous DNA fragmentation and that induced by the potent apoptosis-induced agents colchicine and dexamethasone. These results suggest that prevention of apoptosis is a function of labile Zn, and that a reduction below a threshold concentration in this Zn pool induces apoptosis.
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PMID:Correlation of apoptosis with change in intracellular labile Zn(II) using zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetic acid], a new specific fluorescent probe for Zn(II). 825 31

The mechanism of cell death induced by calcium ionophore, A23187, was investigated in six human leukemia cell lines. Following exposure to 1 microM A23187, the myelogenous cell lines (HL-60, U-937, KG-1) underwent apoptosis within 3 h as determined by their morphology and DNA fragmentation assay. In contrast, T-lymphoblastic leukemia cell lines (Molt-4, Molt-3, CEM) revealed necrotic cell death after 24 h of incubation. However, an initial rise of intracellular free calcium concentrations and growth inhibition after treatment with A23187 were similar in the two cell types. We further showed that an endonuclease capable of mediating internucleosomal DNA fragmentation was constitutively expressed in the cytosol but not in the nuclei of the myelogenous cell lines, although this endonuclease was not detected in either the nuclei or the cytosol of the T-lymphoblastic cell lines. The activation of the endonuclease in myelogenous cells is calcium-independent and has an optimal pH of 7.5-9. It is inhibited by 1 mM zinc ion or 300 microM aurintricarboxylic acid. We propose that this constitutive endonuclease may be related to the susceptibility of myelogenous leukemia cell lines to apoptotic cell death.
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PMID:Different mode of cell death induced by calcium ionophore in human leukemia cell lines: possible role of constitutive endonuclease. 826 92

Serum antioxidant vitamins A (retinol) and E (alpha-tocopherol), beta-carotene, zinc and selenium for 418 children with newly diagnosed malignancy were compared with those of 632 cancer-free controls. Incident cancer cases and controls were 1-16 years old and recruited in 1986-1989. Age- and sex-adjusted serum concentrations of retinol, beta-carotene and alpha-tocopherol were significantly inversely associated with cancer. In similar models, the odds ratio (OR) comparing the highest with the lowest quintile was 2.06 (95% confidence interval [CI] 1.40-3.02) for retinol, 3.87 (95% CI: 2.54-5.90) for beta-carotene, 2.15 (95% CI: 1.48-3.10) for alpha-tocopherol, 1.29 (95% CI: 0.75-2.23) for selenium, and 1.94 (95% CI: 1.17-2.23) for zinc. The cancer sites that were associated with serum beta-carotene were, in general, leukaemia, lymphoma, central nervous system, bone and renal tumours. Moreover, leukaemia was associated with low mean serum levels of retinol, selenium and zinc. Subjects with lymphoma, bone and renal tumours also had lower mean retinol and alpha-tocopherol levels than controls. Brain tumour patients had low vitamin E levels. Low serum values of antioxidant vitamins were associated with childhood neoplasm occurrence. Some site-specific effect was reported. Low peripheral nutrient levels are not considered as cancer promoters but rather as an impairment of the body's defence mechanism occurring during the cancer-related metabolic and nutritional disturbances and inflammation processes.
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PMID:Serum beta-carotene and antioxidant micronutrients in children with cancer. The 'Cancer in Children and Antioxidant Micronutrients' French Study Group. 828 53

It has been reported that in many neoplastic diseases, including leukemia, alterations in plasma zinc levels may frequently occur, although the causes for such alterations have yet to be clearly defined. Since zinc is required to induce biological activity to thymulin (Zn-FTS), a biochemical defined thymic hormone, and marginal zinc deficiencies may prevent its peripheral biological activation, we investigated the plasma level of zinc and of both active thymulin (Zn-FTS) and total zinc saturable thymulin (Zn-FTS + FTS) in 91 young patients affected by acute lymphoblastic leukemia (ALL) at various stages of the disease. It was discovered that the plasma zinc level was reduced at the onset and relapse, whereas in complete remission and in off-therapy it was in the normal range. Total zinc-saturable thymulin concentration did not change during the disease, whereas the active fraction was reduced at the onset and in relapse when compared with values observed in the other stages of the disease or in healthy controls. These data suggest that zinc plasma deficiency is present in ALL patients at the onset and during relapse, and that such a deficiency causes a decrease in the activity of thymulin despite a nearly normal production by the thymus. An impairment of peripheral immune efficiency in ALL patients is commonly found. The existence of positive correlations between zinc or active thymulin and peripheral immunological parameters (phytohemagglutinin [PHA] and concanavalin A [ConA]) at various stages of the disease suggests a link between derangement of peripheral immune function, thymic hormone activity, and zinc failure. These findings, considered together, suggest the possibility of a carefully controlled clinic trial with zinc in ALL patients at the onset and in relapse even in the light of in vitro ineffectiveness of physiological zinc or thymulin concentrations on the duplicative index of human lymphoblastoid cells.
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PMID:Plasma zinc level and thymic hormone activity in young cancer patients. 829 37


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