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 possible existence of several species of DNA-dependent DNA polymerases in mammalian cells in addition to those 2 polymerases which are the smaller enzyme from nucleus and larger one from cytoplasm each having distinct characteristics, have been reported recently. In order to examine the heterogeneity of DNA polymerases in murine leukemia L1210 cells and to characterize their general properties, we have attempted to separate the DNA polymerase activities from L1210 cells. By diethylaminoethyl (DEAE)-cellulose chromatography (0.2 M-1M KCl) of the whole cell extract from L1210 solubilized by 1% Triton X-100 and 0.5 mM ethylenediaminetetraacetate (EDTA), 4 fractions with DNA-dependent DNA polymerase activities were obtained and designated as DD-1, DD-2, DD-3, and DD-4 for eluents with each corresponding concentration of 0.2, 0.3, 0.5, and 0.7 M KCl, respectively. They were distinguishable in properties such as template preference, divalent cation requirement, DNase sensitivity, isoelectric point (pI) and the behavior on the phosphocellulose chromatography. DD-1 preferred native DNA as template exhibiting similar characteristic as nuclear polymerase with low molecular weight and insensitivity to SH-inhibitors. DD-2, DD-3, and DD-4 utilized activated DNA most efficiently, while activity of DD-3 increased even in the presence of DNase 1 under the condition where the others were completely inhibited. Distribution of DNA polymerase activities in the cells is discussed briefly.
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PMID:Separation and properties of DNA polymerase from murine leukemia L1210 cells. 117 38

We have compared the relative inhibitory activity of poly (A) with its analogues poly N6-isopentenyl adenylic acid (poly(i6 A)) and poly N6-benzyl adenylic acid (poly(bzl6A)), and of poly (U) with its analogue poly 2'-fluoro-2'-deoxyuridylic acid (poly(dUfl)), against DNA polymerase, alpha, beta and gamma and terminal deoxynucleotidyl transferase from human cells and two oncorna virus DNA polymerases. Although poly (A) and its analogues were equally inhibitory against endogenous RNA-directed DNA polymerases of murine and feline leukemia viruses, the analogues in contrast to poly (A) were strongly inhibitory against all four cellular enzymes. Poly (dUfl), on the other hand, was up to 100-fold more potent than poly (U) against both viral and cellular enzymes. Since poly (U) at 100 mug/ml and poly (dUfl) at 1 mug/ml had no effect on terminal deoxynucleotidyl transferase while inhibiting other enzymes by 80--100 per cent these polymers could be useful in the characterization and assay of terminal deoxynucleotidyl transferase. In addition, the polymers such as poly (igA) and poly (bzl5A) which were strongly inhibitory to all cellular enzymes, could be useful in cancer chemotherapy if taken up preferentially by the malignant calls due to their high pinocytic activity. The results also demonstrate potential for large variation in inhibitory activity of polyribonucleotides as related to their chemical composition.
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PMID:Modified nucleotide polymers as inhibitors of DNA polymerases. 119 5

Although the mechanisms of therapeutic efficacy of cytosine arabinoside (Ara-C) are multifactorial, the pharmacodynamic basis for its cytotoxicity and therapeutic efficacy lies in its intracellular metabolism and the retention of the active metabolite, Ara-C triphosphate (Ara-CTP), which is a competitive inhibitor of DNA polymerase. Additional determinants of tumor cell sensitivity include Ara-CMP incorporation into cellular DNA, the size of the competing normal metabolite, deoxycytidine/5'-triphosphate pool, and the heterogeneity in growth kinetics of tumor cells, S-phase vs cells in other phases of the cell cycle. With high-dose Ara-C, substantial amounts of Ara-CTP are formed in phases of the cell cycle. The presence of high intracellular concentration with prolonged retention of Ara-CTP could lead to the inhibition of cell growth of the cells entering S-phase as a consequence of inhibition of DNA-polymerase and/or incorporation into cellular DNA, resulting in a chain termination. Pharmacokinetically, Ara-C is rapidly eliminated from plasma. In mice, pharmacokinetic parameters of Ara-C are not sufficient predictors for the observed differences in their in vivo antitumor activity. Although these mice were bearing different tumor types (L1210 Ara-C sensitive or P-388 relatively more resistant), the observed differences in tumor response were achieved under identical plasma Ara-C concentrations and area under the concentration time curve. The observed antitumor activity in L1210 cells is primarily associated with higher Ara-CTP pools and retention (T1/2 > 4 hr) in tumor cells as compared with normal bone marrow cells. In the least responsive tumor (P-388), although Ara-CTP pools were sufficiently high, retention of the drug in tumor cells and in normal cells is poor with a T1/2 < 2 hr. Thus, unlike mice bearing leukemia L1210 cells, alteration of the mode and dose of administration of Ara-C in mice bearing P-388 could only result in increased host toxicity with no therapeutic gain. Similarly in patients with acute nonlymphocyte leukemia (ANLL), there is no significant correlation between plasma Ara-C concentration and the intracellular concentrations or retentions of Ara-CTP. In some patients the highest Ara-CTP pools in leukemic myeloblast cells are achieved at a lower level of plasma Ara-C and decrease further with the increase of plasma Ara-C. Thus, in the in vivo model system and in ANLL patients with no prior chemotherapy, Ara-CTP retention is a critical factor associated with response to this agent, in particular its direct association with duration of complete response.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:1-Beta-arabinofuranosylcytosine in therapy of leukemia: preclinical and clinical overview. 130 93

We have studied a mutant Moloney murine leukemia virus with a deletion in reverse transcriptase (RT) which is predicted to make its RNase H domain resemble structurally that of human immunodeficiency virus RT. This deletion was based on improved RNase H homology alignments made possible by the recently solved three-dimensional structure for Escherichia coli RNase H. This mutant Moloney murine leukemia virus RT was fully active in the oligo(dT)-poly(rA) DNA polymerase assay and retained nearly all of wild-type RT's RNase H activity in an in situ RNase H gel assay. However, proviruses reconstructed to include this deletion were noninfectious. Minus-strand strong-stop DNA was made by the deletion mutant, but the amount of minus-strand translocation was intermediate to the very low level measured with RNase H-null virions and the high level seen with wild-type RT. The average length of translocated minus-strand DNA was shorter for the deletion mutant than for wild type, suggesting that mutations in the RNase H domain of RT also affect DNA polymerase activity.
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PMID:Defects in Moloney murine leukemia virus replication caused by a reverse transcriptase mutation modeled on the structure of Escherichia coli RNase H. 137 May 51

Proliferative cell fractions were measured by flow cytometry in 20 patients with acute leukemia, 4 with chronic myelocytic leukemia in blastic crisis and 7 with malignant lymphoma. The cells were fixed with 2% paraformaldehyde followed by staining with fluorescein isothiocyanate conjugated monoclonal antibody against DNA polymerase a. The DNA polymerase a-positive population was widely distributed in leukemia, from 20.4% to 84.7% in peripheral blood and from 6.5% to 92.5% in the bone marrow. A positive correlation was found between the values in peripheral blood and bone marrow. The values ranged from 66.4% to 88.1% in cells from cases of malignant lymphoma. Cryopreserved cells may be available for measurement of DNA polymerase a because the result obtained in both frozen and fresh cells were essentially the same.
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PMID:[Detection of proliferative cells by DNA polymerase a as a proliferation associated marker]. 144 3

The BCL-2 (B-cell lymphoma/leukemia-2) gene is frequently involved in t(14;18) translocations in non-Hodgkin's lymphomas and encodes a 26-kDa intracellular, membrane-associated protein. Expression of the BCL-2 gene has previously been correlated with cellular proliferation in normal and neoplastic lymphoid cells under a variety of experimental conditions. To examine the regulation of p26-BCL-2 protein levels during the cell cycle, we utilized the method of counterflow centrifugal elutriation to enrich for cells in various phases of the cell cycle. Relative levels of p26-BCL-2 protein were measured by immunoblotting, and comparisons were made with a cell cycle-regulated protein, p62-CYCLIN-A, and a protein whose levels are constant throughout the cell cycle, p36-PCNA (DNA polymerase-delta auxiliary factor). Relative levels of p26-BCL-2 and p36-PCNA did not vary among cell fractions enriched for specific phases of the cell cycle, whereas p62-CYCLIN-A was elevated in late S- and G2/M-phase cells. Similar results were obtained with lymphoma and leukemia cell lines that have either normal or translocated BCL-2 genes. These results obtained by elutriation were confirmed by pharmacologically inducing cell cycle arrest in proliferating lymphoid cell lines with hydroxyurea, quercetin, and nocodazole which blocked cells at S, G2, and M phases, respectively. Taken together, the data indicate that p26-BCL-2 is not a true cell cycle-regulated protein, although its levels can fluctuate in connection with changes in rates of cellular proliferation under some circumstances.
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PMID:Cell cycle analysis of p26-BCL-2 protein levels in proliferating lymphoma and leukemia cell lines. 158 93

Reverse transcription of the retroviral RNA genome begins with tRNA-primed synthesis of a minus-strand DNA, which subsequently acts as the template for the synthesis of plus-strand DNA. This plus-strand DNA is initiated at a unique location and makes use of a purine-rich RNA oligonucleotide derived by RNase H action on the viral RNA. To determine the variables that are relevant to successful specific initiation of plus-strand DNA synthesis, we have used nucleic acid sequences from the genome of Rous sarcoma virus along with three different sources of RNase H: avian myeloblastosis virus DNA polymerase, murine leukemia virus DNA polymerase, and the RNase H of Escherichia coli. Our findings include evidence that specificity is controlled not only by the nucleic acid sequences but also by the RNase H. For example, while the avian reverse transcriptase efficiently and specifically initiates on the sequences of the avian retrovirus, the murine reverse transcriptase initiates specifically but at a location 4 bases upstream of the correct site.
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PMID:Specificities involved in the initiation of retroviral plus-strand DNA. 168 26

S-Antigen (S-Ag) is a well characterized 45,000 m.w. photoreceptor cell protein. When injected into susceptible animal species, including primates, it induces an experimental autoimmune uveitis, a predominantly T cell-mediated autoimmune disease of the retina and uveal tract of the eye, and of the pineal gland. In this study we found an amino acid sequence homology between a uveitopathogenic site of S-Ag, several viral proteins and one additional nonviral protein. An experimental autoimmune uveitis and pinealitis was induced in Lewis rats with these different synthetic peptides, corresponding to the amino sequence of hepatitis B virus DNA polymerase, gag-pol polyprotein of Baboon endogenous virus and gag-pol polyprotein of AKV murine leukemia virus and potato proteinase inhibitor IIa, which contain three or more consecutive amino acids identical to peptide M in S-Ag. Lymph node cells from rats immunized with either peptide M or the different synthetic peptides showed a significant degree of cross-reaction. Mononuclear cells from monkeys (Macaca fascicularis) immunized with peptide M also showed significant proliferation when incubated with either peptide M or synthetic peptides as measured by in vitro lymphocyte mitogenesis assay using [3H]TdR. Based on our findings we conclude that a viral infection may sensitize the mononuclear cells that can cross-react with self proteins by a mechanism termed molecular mimicry. Tissue injury from the resultant autoantigenic event can take place in the absence of the infectious virus that initiated the immune response.
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PMID:Molecular mimicry between a uveitopathogenic site of S-antigen and viral peptides. Induction of experimental autoimmune uveitis in Lewis rats. 168 49

We have constructed a series of plasmids that, when introduced into Escherichia coli, induce the expression of high levels of either wild-type or mutated forms of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). Mutant forms of RT that had been previously analyzed for their RNA-dependent DNA polymerase activity were tested for RNase H activity using an in situ polyacrylamide gel assay. Mutations affecting the RNase H are not clustered in a single region of the 66-kDa RT molecule. With only few exceptions, mutations that affect the RNase H activity also cause a substantial decrease in the DNA polymerase function. This suggests that, unlike the RT from murine leukemia virus (MuLV), it is difficult to genetically separate the catalytic domains responsible for the RNase H and DNA polymerase functions of HIV-1 RT. Those few mutations that differentially affect the RNase H and the polymerase activities of HIV-1 RT suggest that, as in MuLV, the polymerase domain is in the amino-terminus and the RNase H domain is in the carboxy-terminus. We have also generated chimeric molecules that are composed of sequences from the RT of HIV-1 and MuLV and these hybrid RTs were analyzed for their enzymatic properties. Two of these chimeric RTs possess RNase H activity but lack detectable DNA polymerase activity.
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PMID:Mutational analysis of the ribonuclease H activity of human immunodeficiency virus 1 reverse transcriptase. 169 64

Within normal hemopoiesis, the intranuclear DNA polymerase TdT seems to be exclusively expressed by T and B lymphoid precursor cells. Double staining experiments showed that TdT can also be expressed in blast cells of certain acute myeloid leukemias. Recent reports described a very strong association between TdT expression and rearrangements of IgH and TcR genes in such AML specimens, suggesting a predominant lymphoid commitment of these TdT positive AML blasts. When submitting 24 serologically and morphologically well-characterized TdT positive AML specimens for additional genotypic analysis to determine the IgH and TcR gene configuration, we observed that only four had clonally rearranged IgH and/or TcR genes, whereas 20 had germ line configuration. This frequency is clearly lower than previously reported and not necessarily different from rearrangement frequencies reported for TdT negative AML (4-40%). It would seem to us, therefore, that the expression of TdT in otherwise well-defined AML blasts is not necessarily associated with a higher frequency of immunoglobulin and/or T cell receptor gene rearrangement.
Leukemia 1990 Apr
PMID:Terminal deoxynucleotidyl transferase and CD7 expression in acute myeloid leukemias are not associated with a high frequency of immunoglobulin and/or T cell receptor gene rearrangement. 169 41


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