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)

In order to study the antigenicity of envelope 46 kDa glycoprotein (gp46) of human T-cell leukemia virus type-I (HTLV-1), we have generated monoclonal anti-gp46 antibodies (MAbs), REY-7, REY-11, REY-16, REY-30, MET-2 and MET-3 from rats and mice. Immunoblot and immunofluorescence assays showed that these MAbs recognize gp46 and its related antigens, and specifically stained HTLV-I-bearing cells. All MAbs reacted with a recombinant gp46 antigen, N147, expressing the 147 amino acids in the C-terminal half of gp46. By using various synthetic peptides corresponding to the gp46 sequence, epitopes recognized by REY-7 and MET-3, REY-11 and REY-16, and REY-30 were mapped to regions corresponding to the amino acids 175-199, 253-282 and 288-312, respectively. MET-2 did not react with any of the peptides used. These results indicate that the present MABs are directed against at least 4 distinct epitopes expressed on the C-terminal half of gp46. The binding of these MAbs to gp46 was specifically inhibited by sera from HTLV-I-infected individuals, but none of these MAbs inhibited the cell fusion activity of HTLV-I.
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PMID:Generation and characterization of monoclonal antibodies against multiple epitopes on the C-terminal half of envelope gp46 of human T-cell leukemia virus type-I (HTLV-I). 169 31

The antigen CD10 (common acute lymphoblastic leukaemia antigen), which is the zinc metalloprotease, neutral endopeptidase 24.11 (also known as NEP or 'enkephalinase'), is expressed by acute lymphoblastic leukaemias, normal lymphoid progenitors, mature polymorphonuclear leukocytes and certain nonhaematopoietic cells. CD10/NEP hydrolyses several naturally occurring peptides, including the endogenous opioid pentapeptides Met- and Leu-enkephalin. In invertebrate organisms such as the mollusc Mytilus edulis, Met-enkephalin triggers inflammatory responses by inducing morphological changes, directed migration and aggregation of haemocytes. We report here that a structure related to CD10/NEP is expressed by M. edulis haemocytes and that abrogation of CD10/NEP enzymatic activity reduces the amount of Met-enkephalin required for haemocyte activation by five orders of magnitude. Similar results are obtained with CD10+ human polymorphonuclear leukocytes, indicating that CD10/NEP related structures regulate enkephalin-mediated inflammatory responses in organisms whose ancestors diverged approximately 500 million years ago.
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PMID:Downregulation of enkephalin-mediated inflammatory responses by CD10/neutral endopeptidase 24.11. 169 30

The glycoproteins on the surface of HL-60/S wild-type, drug-sensitive human leukemia cells and HL-60/AR anthracycline-resistant cells which do not overexpress the P-glycoprotein, were characterized by labeling with [35S]-methionine, NaB[3H4], phosphorus 32, or sodium iodide I 125. HL-60/S and HL-60/AR cell lysates and membrane fractions tagged with [35S]-methionine or phosphorus 32 showed no significant differences in their protein patterns as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and by autoradiography. HL-60/S cells labeled with NaB[3H4] yielded glycoproteins that were smeared predominantly in the molecular-weight range of 210,000 and 160,000 Da, with pI values ranging between pH 4 and pH 4.4. In contrast, NaB[3H4]-labeled HL-60/AR cells showed 7-8 discrete glycoproteins within a molecular-weight range of 170,000 and 140,000 Da, with pI values also ranging between pH 4 and pH 4.4. In addition, [3H]-glucosamine incorporation into HL-60/S and HL-60/AR cells revealed that the latter showed lower uptake of [3H]-glucosamine than did the former. Following treatment with tunicamycin, [3H]-glucosamine uptake in HL-60/S cells decreased, whereas that in HL-60/AR cells remained unchanged. Surface-membrane radioiodination of HL-60/S and HL-60/AR cells showed two distinct protein electrophoretic patterns, with differences being observed in both the high-(220-95 kDa) and low-molecular-weight ranges (21 kDa). Flow cytometric analysis of HL-60/S and HL-60/AR cells using myeloid and lymphoid antigen-specific antibodies demonstrated no antigenic differences between HL-60/S and HL-60/AR cells. HL-60/S cells incubated in the presence of tunicamycin, an inhibitor of N-linked glycosylation, or the protein kinase C agonist phorbol 12-myristate 13-acetate (PMA) developed a glycoprotein pattern similar to that observed in HL-60/AR cells. In addition, tunicamycin treatment of HL-60/S cells decreased daunorubicin (DNR) retention and altered its intracellular distribution as compared with that in HL-60/AR cells. These data indicate that HL-60/AR cells do not possess either de novo or amplified high-molecular-weight surface-membrane proteins; instead, existing proteins are hypoglycosylated. These results also show that HL-60/AR cells exhibit the multidrug-resistant phenotype in association with altered membrane glycoproteins of both high (220-95 kDa) and low molecular weight (21 kDa), but without overexpression of the P-glycoprotein. Furthermore, in HL-60/S cells, the multidrug-resistant phenotype is partially inducible by inhibition of N-linked glycosylation of cell-surface proteins.
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PMID:Membrane glycoprotein changes associated with anthracycline resistance in HL-60 cells. 171 35

The specificity of the p15 proteinase of myeloblastosis-associated virus (MAV) was tested with nonviral high molecular weight substrates and with synthetic peptides. Peptides with sequences spanning known cleavage sites in viral polyproteins of Rous sarcoma virus (RSV) and avian leukemia viruses, as well as in BSA and HSA, were synthesized, and the rate of their cleavage by the MAV proteinase was compared. Synthetic peptides require for successful cleavage at least 4 residues at the N-terminal side and 3 residues at the C-terminal side. The proteinase shows a preference for hydrophobic residues with bulky side chains (Met, Tyr, Phe) in P3, although Arg and Gln can also be accepted. Small hydrophobic residues are required in P2 and P2', and large hydrophobic residues (Tyr, Met, Phe/p-nitro-Phe) are preferred in both P1 and P1'. The difference between the specificity of the p15 proteinase and that of the HIV-1 proteinase mostly pertains to position P2' of the substrate, where bulkier side chains are accepted by the HIV-1 proteinase (Richards et al., 1990). A good chromogenic substrate for the MAV and RSV proteinases was developed and used to further characterize the MAV proteinase activity with respect to ionic strength and pH. The activity of the proteinase is strongly dependent on ionic strength and pH. Both the kcat and Km values contribute to a higher cleavage efficiency at higher salt concentrations and show a bell-shaped pH dependence curve with a sharp maximum at pH 5.5 (kcat) and 6.5 (Km).
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PMID:Specificity studies on retroviral proteinase from myeloblastosis-associated virus. 184 25

Human promyelocytic leukaemia (HL-60) cells were employed to study the induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme in controlling prostaglandin inactivation. Phorbol 12-myristate 13-acetate (PMA) stimulated 15-PGDH activity in a time- and concentration-dependent manner. Dimethyl sulphoxide (DMSO) also stimulated the enzyme activity, although a much delayed stimulation was observed. Western blot studies indicated that PMA increased significantly a 28 kDa immunoreactive protein characteristic of 15-PGDH. L-[35S]Methionine labelling of the PMA-treated cells showed a similar enhancement over the control cells. These studies indicate that PMA induced synthesis of 15-PGDH. Stimulation of 15-PGDH activity by PMA or DMSO appears to be mediated by protein kinase C activation, since an inactive analogue of PMA failed to induce the effect, and both staurosporine and H-7 blocked the stimulation. Stimulation by PMA was optimal at 10 nM and less effective at higher concentrations. Western blot studies indicated that a similar, if not greater, amount of enzyme protein was induced at high concentrations of PMA, suggesting that enzyme inactivation might be occurring. Possible enzyme inactivation by protein kinase C activation was further examined by incubating DMSO-treated cells with a high concentration of PMA (50 nM). Time-dependent inactivation of 15-PGDH within the first 1 h was observed and this inactivation was partially blocked by staurosporine and H-7. Pulse-chase experiments indicated that 15-PGDH had a rapid turnover rate (t 1/2 = 47 min), and PMA shortened the half-life of the enzyme (t 1/2 = 33 min), suggesting that PMA might have an additional effect on 15-PGDH degradation. The rapid turnover of 15-PGDH indicates that the enzyme activity depends on continued enzyme synthesis, and this could be susceptible to hormone and drug control mechanisms.
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PMID:Stimulation of synthesis de novo of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase in human promyelocytic leukaemia (HL-60) cells by phorbol ester. 195 49

Plasma homocysteine was determined in 12 children with acute lymphoblastic leukemia. The patients were investigated prior to chemotherapy (stage I), during seven weeks of induction chemotherapy (stage II), and thereafter during intermittent high-dose methotrexate (HD-MTX) therapy (stage III). The patients were followed for a period of three to 15 months, and the study included a total of 80 HD-MTX courses. Before start of chemotherapy (stage I), the average plasma homocysteine level in the children with leukemia was 13.18 +/- 6.23 (SD) mumol/liter, which is significantly (P less than 0.001) higher than the level in control children (6.52 +/- 1.21 mumol/liter). The plasma homocysteine level in the patients was positively correlated with the peripheral white blood cell count (P less than 0.01) and negatively correlated with serum folate (P less than 0.02). The serum folate was normal or subnormal in these patients. During induction therapy with cytotoxic drugs such as vincristine, asparaginase, and intrathecal MTX (stage II), there was a drastic change in plasma homocysteine as a function of time. A reciprocal alteration in serum folate was observed, suggesting fluctuating intracellular folate status at this stage of therapy. At the end of stage II (about seven weeks), there was a significant (P less than 0.01) reduction in total homocysteine (to 7.08 +/- 3.84 mumol/liter). HD-MTX (8 g/m2) therapy with 5-formyltetrahydrofolate "rescue" (stage III) was usually begun about seven weeks after start of chemotherapy, and the patients were followed for two to eight courses separated by three to eight weeks. Plasma homocysteine showed a transient increase (26-64%) following each MTX infusion. After three MTX infusions, basal total plasma homocysteine was reduced to 5.56 +/- 1.12 mumol/liter. During most MTX infusions, there was a variable reduction (17-56%) in plasma methionine followed by a rebound increase. It is concluded that plasma homocysteine in children with acute lymphoblastic leukemia is elevated prior to therapy, probably because of occasional folate deficiency and increased burden of proliferating cells. During induction therapy, monitoring plasma homocysteine and serum folate both suggest a labile folate homeostasis, usually a deficiency state. HD-MTX induced a temporary intracellular folate depletion before 5-formyl-tetrahydrofolate was administered, as judged by a transient homocysteinemia. The methionine depletion may interfere with the antileukemic effect of MTX.
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PMID:Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate. 198 22

The inability of cells in culture to grow in medium where methionine is replaced by its metabolic precursor, homocysteine, has been linked to neoplastic transformation and termed 'methionine dependence' or 'methionine auxotrophy'. The present investigation was undertaken to establish the influence of intracellular glutathione level on methionine auxotrophy in different mouse cell lines. A non-transformed, methionine-independent fibroblast cell line with essential normal growth rate in methionine-deficient, homocysteine-supplemented medium (Met-Hcy+), showed only a slight initial lag and then the same growth as control when glutathione was reduced to less than 5% by the glutathione synthesis inhibitor buthionine sulfoximine (BSO). Increasing cellular glutathione by cystamine in a completely methionine-dependent leukemia cell line did not stimulate the cells to proliferate in Met-Hcy+ medium. A partly methionine-dependent transformed fibroblast cell line with reduced capacity to proliferate in Met-Hcy+ medium showed increased growth potential when the cells were depleted of glutathione by a non-toxic concentration of BSO. An even higher growth potential of these cells in Met-Hcy+ medium was obtained by addition of a non-toxic concentration of cystamine, while only a transient increase of glutathione content was observed under these conditions. Both BSO and cystamine increased the fraction of protein-bound cysteine and homocysteine in the partly methionine-dependent cells. These metabolic alterations correlated with the increased ability of these cells to utilize homocysteine for growth. Our results suggest that methionine auxotrophy is a metabolic defect that is not related to the cellular glutathione status, but may be related to the intracellular distribution between free and protein-bound forms of other thiols as cysteine and homocysteine.
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PMID:Modulation of glutathione content and the effect on methionine auxotrophy and cellular distribution of homocysteine and cysteine in mouse cell lines. 199 90

Heterogeneity of p53 protein expression is seen in blast cells of patients with acute myelogenous leukemia (AML). p53 protein is detected in the blasts of certain AML patients but not in others. We have identified p53 protein variants with abnormal mobility on gel electrophoresis and/or prolonged half-life (t 1/2). We have sequenced the p53 coding sequence from primary blast cells of five AML patients and from the AML cell line (OCIM2). In OCIM2, a point mutation in codon 274 was identified that changes a valine residue to aspartic acid. A wild type p53 allele was not detected in these cells. Two point mutations (codon 135, cysteine to serine; codon 246, methionine to valine) were identified in cDNA from blasts of one AML patient. Both mutations were present in blast colonies grown from single blast progenitor cells, indicating that individual leukemia cells had sustained mutation of both p53 alleles. The cDNAs sequenced from blast samples of four other patients, including one with prolonged p53 protein t 1/2 and one with no detectable p53 protein, were fully wild type. Thus, the heterogeneity of p53 expression cannot be explained in all cases by genetic change in the p53 coding sequence. The prolonged t 1/2 of p53 protein seen in some AML blasts may therefore reflect changes not inherent to p53. A model is proposed in which mutational inactivation of p53, although not required for the evolution of neoplasia, would confer a selective advantage, favoring clonal outgrowth during disease progression.
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PMID:Mutation of the p53 gene in human acute myelogenous leukemia. 200 69

A total of 3430 polypeptides (2592 cellular; 838 secreted) from transformed human amnion cells (AMA) labeled with [35S]methionine were separated and recorded using computer-aided two-dimensional (2-D) gel electrophoresis. A master 2-D gel database of cellular protein information that includes both qualitative and quantitative annotations has been established. The protein numbers in this database differ from those reported in an earlier version (Celis et al. Leukemia 1988, 2,561-602) as a result of changes in the scanning hardware. The reported information includes: percentage of total radioactivity recovered from the gels (based on quantitations of polypeptides labeled with a mixture of 16 14C-amino acids), protein name (including credit to investigators that aided identification), antibody against protein, cellular localization, (nuclear, 40S hnRNP, 20S snRNP U5, proteasomes, endoplasmic reticulum, mitochondria, Golgi, ribosomes, intermediate filaments, microfilaments and microtubules), levels in fetal human tissues, partial protein sequences (containing information on 48 human proteins microsequenced so far), cell cycle-regulated proteins, proteins sensitive to interferons alpha, beta, and gamma, heat shock proteins, annexins and phosphorylated proteins. The results presented should be considered as the initial phase of a joint effort between our laboratories to undertake a general and systematic analysis of human proteins. Using this integrated approach it will be possible to identify phenotype-specific proteins, to microsequence them and store the information in the database, to identify the corresponding genes, to search for homology with previously characterized proteins and to study the function of groups of proteins (pathways, organelles, etc.) that exhibit interesting regulatory properties. In particular, the 2-D gel protein database may become increasingly important in view of the concerted effort to map and sequence the entire human genome.
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PMID:Comprehensive two-dimensional gel protein databases offer a global approach to the analysis of human cells: the transformed amnion cells (AMA) master database and its link to genome DNA sequence data. 209 Apr 60

Glycoproteins from the human T leukemia cells Jurkat were found to bind to the GalNAc alpha 1----Ser/Thr-specific lectin from Salvia sclarea seeds. The analysis of the O-linked saccharides of immunopurified leukosialin, the major [3H]glucosamine-labeled glycoprotein in Jurkat cell lysate, revealed the presence of mainly GalNAc alpha 1----Ser/Thr with only minor amounts (approximately 17%) of more complex O-glycans. A comparison between Jurkat and K562 cell glycosyltransferase involved in the biosynthesis of O-linked carbohydrates showed that a markedly lower activity of UDP-Gal:GalNAc alpha 1----Ser/Thr beta 1----3galactosyltransferase is apparently responsible for the presence of truncated O-glycans in the Jurkat cell line. The O-glycosylation defect makes Jurkat cells an ideal model to study the initiation of O-linked saccharides. Pulse-chase experiments with [35S] methionine showed that the addition of GalNAc to leukosialin is responsible for the decreased mobility of the mature glycoprotein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Furthermore, no biosynthetic intermediates between the O-glycan-free precursor and the fully O-glycosylated form could be detected either with an anti-leukosialin antiserum or with the GalNAc-specific lectin. Lowering the chase temperature to 15 degrees C completely inhibited the transfer of GalNAc to the peptide core indicating that O-glycan initiation takes place in the first Golgi elements and not in transitional vesicles between endoplasmic reticulum and Golgi. In addition, treatment of the cells with monensin did not inhibit GalNAc transfer to leukosialin apoprotein. These results indicate that the initiation of O-glycosylation in Jurkat cells starts in the cis-Golgi stacks.
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PMID:Biosynthesis of truncated O-glycans in the T cell line Jurkat. Localization of O-glycan initiation. 214 May 70


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