Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HL-60 promyelocytic leukemia cell line is resistant to nitrosoureas and contains high levels of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase). We examined the protective role of the alkyltransferase in the nitrosourea resistance observed in this myeloid leukemia cell line to determine whether inactivation of the alkyltransferase with the modified base, O6-methylguanine (O6mGua), could sensitize these cells to nitrosoureas. The HL-60 cells were sensitized approximately 3.0-fold to five different nitrosoureas when the alkyltransferase was inactivated by 88% following a 24-h preincubation in 0.5 mM O6mGua. No effect of O6mGua preincubation was observed in the K562 chronic myelogenous leukemia cell line which is sensitive to nitrosoureas and has low levels of alkyltransferase activity. When regeneration of HL-60 alkyltransferase activity after exposure to nitrosoureas was prevented by maintaining cells in O6mGua, HL-60 became even more sensitive (3.7- to 8.5-fold) to nitrosoureas but remained slightly more resistant than K562. Next, we compared the dose of methyl- and chloroethylnitrosoureas which were cytotoxic in HL-60 with the dose which caused repair-induced inactivation of the alkyltransferase. Both methyl- and chloroethyl-nitrosoureas caused the dose-dependent inactivation of the alkyltransferase and with both, cytotoxicity was increased with O6mGua exposure. However, chloroethylnitrosoureas, which form a variety of O6 alkylation adducts, some of which are poorly repaired, exhibited 7-12 times more cytotoxicity relative to repair-induced inactivation of the alkyltransferase whereas methylnitrosoureas became cytotoxic only when the alkyltransferase had been inactivated. These data suggest that leukemic cells are sensitized to both methyl- and chloroethylnitrosoureas when O6mGua is used to persistently inactivate the alkyltransferase. However, the alkyltransferase provides more efficient protection from methylnitrosoureas than chloroethylnitrosoureas most likely because the latter form adducts which are poorly repaired by the protein and which if unrepaired may become cytotoxic cross-links.
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PMID:Potentiation of nitrosourea cytotoxicity in human leukemic cells by inactivation of O6-alkylguanine-DNA alkyltransferase. 316 97

A novel antibiotic tautomycin induced many blebs on the surface of K562 human chronic myeloid leukemia cells, similar to the morphological changes induced by phorbol esters. However, tautomycin did not induce nitroblue tetrazolium reducing activity, when HL60 human promyelocytic leukemia cells were caused to differentiate by quinomycin into mature granulocytes. It did not induce spread of HL60 cells, one of the phenotypes of mature macrophages. In addition, it did not compete with phorbol dibutyrate to bind to the cell surface of K562 cells. However, tautomycin significantly activated protein kinase C (PKC) extracted from K562 cells. These results indicate that tautomycin is a new activator of PKC, distinct from phorbol esters.
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PMID:Induction of morphological change of human myeloid leukemia and activation of protein kinase C by a novel antibiotic, tautomycin. 316 53

Myeloblasts from the blood of patients with chronic myeloid leukemia (CML) in a blastoid crisis were shown to have an imbalance in the ribonucleotide pools compared with normal blood neutrophils. This imbalance includes decreased ratios of purine:pyrimidine, adenine:guanine, and uracil:cytosine nucleotides as well as an increased relative concentration and a changed composition of the uridine diphosphate (UDP) sugars, with relatively more UDP-N-acetylhexosamines. Similar, more prominent deviations were found in HL-60 promyelocytic leukemia cell line cells. We have used HL-60 cells to investigate the relationships between these changes in the ribonucleotide pools and myelocyte proliferation, maturation, and/or transformation to the malignant state. When HL-60 cells were separated by elutriation centrifugation into fractions enriched in G1, S phase, or G2 + M, we found only differences in the amount of nucleotides per cell (G2 + M greater than S phase greater than G1) corresponding with the increase in cell volume but not in the qualitative composition of the nucleotides. Therefore, throughout this study, the nucleotide content of all cells was calculated per unit of cell volume. When HL-60 cells were induced to myeloid differentiation with dimethyl sulfoxide, proliferation stopped after 3 days. After 6 days, 70-90% of the cells had matured into cells capable of nitro blue tetrazolium reduction upon stimulation with phorbol myristate acetate. During the maturation process, the mean volume of the HL-60 cells decreased, and the nucleotide content and the purine:pyrimidine and adenine:guanine nucleotide ratios increased. The composition of the UDP sugars changed dramatically, with a decrease of UDP-N-acetylhexosamines and an increase of UDP-hexoses. Similar changes were detected in HL-60 cells that stopped proliferating without dimethyl sulfoxide-induced maturation, except that the UDP sugar composition showed an increase of UDP-N-acetylhexosamines and a decrease of UDP-hexoses. Careful examination of these results indicates that the decreased ratio of purine:pyrimidine nucleotides and the decreased ratio of uracil:cytosine nucleotides observed in CML myeloblasts may be regarded as specific changes caused by transformation of myelocytes to the malignant state. The increased amount of UDP-N-acetylhexosamines and total UDP sugars in the CML cells may also be connected with the transformation process. All other deviations in the nucleotide pattern of transformed myelocytes in comparison to that of mature, normal neutrophils can be explained by the state of proliferation and/or immaturity of CML myeloblasts and HL-60 cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Imbalance in the nucleotide pools of myeloid leukemia cells and HL-60 cells: correlation with cell-cycle phase, proliferation, differentiation, and transformation. 346 22

Lactoferrin is a major constituent of polymorphonuclear leukocyte granules and is present in mature neutrophils but not in blasts or promyelocytes. We have isolated a cDNA probe for lactoferrin and used it to study the synthesis of lactoferrin mRNA by normal and leukemic granulocyte precursors. The probe pHL-41 has been subcloned in phage m13 and characterized by restriction endonuclease analysis and nucleic acid sequencing. pHL-41 contains approximately 40% of the coding sequence of the lactoferrin gene. The 3' untranslated region includes a stop codon and a possible polyadenylation signal. There is a greater than 98% agreement between the cDNA-deduced amino acid sequence and that determined by analysis of the protein. Myeloid cells from normal bone marrow and circulating leukocytes from patients with chronic granulocytic leukemia contain lactoferrin mRNA transcripts that are indistinguishable in size and relative quantity. The human promyelocytic leukemia cell line HL-60 contains no lactoferrin mRNA. Induction of monocytic or granulocytic differentiation fails to induce the synthesis of detectable lactoferrin message. Similarly, studies with the human myeloblastic leukemia cell line PLB-985 reveal the inability of these cells to produce lactoferrin mRNA even under conditions that bring about morphologically demonstrable granulocytic differentiation. These data suggest that granulocytic differentiation in the leukemic cell lines is incomplete or defective. The presence of lactoferrin may play a role in the orderly expression of the genetic program leading to the development of the normal mature granulocyte.
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PMID:Isolation of lactoferrin cDNA from a human myeloid library and expression of mRNA during normal and leukemic myelopoiesis. 347

Effects of a 7-day treatment with the maturational agents DMF and sodium butyrate on enzymes of pyrimidine metabolism, growth rate and cell maturation were assessed in 5 human tumor cell lines, ARH-77 (myeloma), K-562 (chronic myeloid leukemia), KG-1 (myeloid leukemia), HL-60 (promyelocytic leukemia) and RWLy-1 (non-Hodgkin's lymphoma). DMF lengthened the doubling times of all five cell lines while sodium butyrate lengthened only those of K-562, HL-60 and RWLy-1. Full maturation was induced only in HL-60 by either agent and in K-562 by butyrate. Exposure resulted in a decreased activity of the anabolic enzyme orotate phosphoribosyltransferase (EC 2.4.2.10) and increased activities of the catabolic enzymes thymidine phosphorylase (EC 2.4.2.4) and dihydrouracil dehydrogenase (EC 1.3.1.2). Changes in the amphibolic enzyme, uridine phosphorylase (EC 2.4.2.3) did not follow any apparent pattern. This study indicates that the pattern of pyrimidine metabolism differs between the differentiated and slowly growing, and undifferentiated rapidly growing counterpart of several human tumors, suggesting that enzymes of pyrimidine metabolism can be used as markers for cellular growth and/or maturity.
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PMID:Effects of N,N-dimethylformamide and sodium butyrate on enzymes of pyrimidine metabolism in cultured human tumor cells. 368 65

Changes in glycosphingolipid (GSL) composition during differentiation of human leukemic granulocytes were investigated qualitatively and quantitatively in immature and mature granulocytic cells derived from human chronic myelogenous leukemia (CML) cases and were compared with those found in the in vitro granulocytic differentiation of the human promyelocytic leukemia HL-60 cell line. Two neutral GSLs, ceramide monohexoside and ceramide dihexoside, and two molecular species of gangliosides, one being the ganglio-series ganglioside NeuAc(alpha 2-3)Gal(beta 1-4)Glc-Cer (GM3) and the other being the lacto-series sialosylparagloboside, were predominant in the granulocytic cells at an early maturation stage. During the granulocytic differentiation of CML cells, the contents of ceramide dihexoside and paragloboside increased strikingly with a concomitant decrease in ceramide monohexoside, and the total amount of neutral GSLs increased to about three times as much as that of the most immature granulocytic cells, myeloblasts. On the other hand, lacto-series gangliosides, with longer sugar moieties increased with a concomitant decrease in ganglio-series ganglioside GM3, and the ganglioside profile became more complex. The total content of ganglioside increased in parallel with the complexity of the ganglioside profile. Similar differentiation-associated changes were also found in GSL composition during the in vitro granulocytic differentiation of HL-60 cells. However, a marked difference between the differentiation-dependent change in the GSL composition of CML cells and that of HL-60 cells was observed for a ganglioside species which was found to be one of the major gangliosides in normal neutrophils: in the former, the ganglioside level increased up to the level in normal mature granulocytes as the cells differentiated; in contrast, it decreased significantly during granulocytic differentiation of the latter cells. When the GSL composition of the neutrophils obtained from CML cells, which were apparently normal as to morphology, stimulus-induced membrane potential changes, and superoxide-producing capacity, was compared with that of normal neutrophils, an obvious difference was observed between them, especially with regard to ganglioside GM3; the amount of ganglioside GM3 in the former was about one-sixth of that in the latter. This finding indicates some alterations in the cell membrane structure of neutrophils of CML origin.
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PMID:Changes in glycosphingolipid composition during differentiation of human leukemic granulocytes in chronic myelogenous leukemia compared with in vitro granulocytic differentiation of human promyelocytic leukemia cell line HL-60. 386 27

Cells from 95 patients with acute leukemia were studied by cytochemistry, light microscopy, and transmission electron microscopy (TEM), and were classified according to the French-American-British (FAB) guidelines. This group included 63 patients with acute nonlymphocytic leukemia (ANLL) de novo, 18 with acute lymphocytic leukemia (ALL), and 14 with ANLL as a second malignancy. In addition, 13 cases of chronic myelocytic leukemia in blast crisis were studied. Ultrastructural examination resulted in reclassification of 6 cases of ANLL de novo; two of these were reclassified from M2 (myeloblastic leukemia with maturation) to M3 variant (microgranular variant of hypergranular promyelocytic leukemia). The classification of the cases of CML in blast crisis was identical by light microscopy and TEM. IN 1 case of myeloblastic crisis, however, basophilic granules were demonstrated by TEM but were not appreciated by light microscopy. Classification of the cases of secondary leukemia was possible by light microscopy and cytochemistry in all 14 cases, but was often difficult since the cytochemical reactions were usually less intense than in de novo ANLL. This was particularly true in those cases classified as M1, and in such cases, TEM was required to confirm the diagnosis.
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PMID:Ultrastructural characterization of de novo and secondary leukemias. 612 30

There is evidence that polymorphonuclear granulocytes release neutral proteinases such as elastase (E) and cathepsin G in the course of acute leukemia. These proteinases may inactivate clotting factors by unspecific degradation before they are eliminated via complex formation with endogenous inhibitors, e.g. the alpha 1-proteinase inhibitor (alpha 1-PI). In this study it was attempted to correlate plasma levels of the E-alpha 1-PI complex with factor XIII and antithrombin III in acute leukemia. Using a newly developed, sensitive enzyme-linked immunoassay the concentration of E-alpha 1-PI in patients with various types of leukemia, malignant lymphoma or multiple myeloma was determined. Only patients with acute myelocytic or promyelocytic leukemia (AML, APL) and chronic myelocytic leukemia with and without blastic transformation (CML) showed moderate to high levels of E-alpha 1-PI (2- to 20-fold of normal). However, coagulation factor concentration observed in the different types of leukemia seemed to be independent of elastase liberation. Most of the AML-patients with elevated E-alpha 1-PI levels showed peroxidase positive blood cell smears.
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PMID:Plasma levels of human granulocytic elastase alpha 1-proteinase inhibitor complex (E-alpha 1-PI) in leukemia. 637 1

A murine hybridoma-derived monoclonal antibody, PM-81, was obtained from a fusion of cells of the NS-1 myeloma cell line with cells from a mouse immunized with the HL-60 promyelocytic leukemia cell line. This cytotoxic IgM monoclonal antibody was specific for myeloid cells. Employing indirect immunofluorescence and flow cytometry, we determined that this antibody reacts strongly with normal human granulocytes, eosinophils, and monocytes but not lymphocytes (including phytohemagglutinin-activated lymphocytes), null cells, red blood cells, or platelets. Moreover, the PM-81 antibody reacts with leukemia cells from 19 of 22 patients with acute myelocytic leukemia of all FAB subclasses, three of three patients with common acute lymphocytic leukemia, four of four patients with chronic myelocytic leukemia (CML) in myeloid blast crisis (terminal transferase (TdT)-negative) but did not react with cells from two patients with CML in lymphoid blast crisis (TdT-positive) or five patients with chronic lymphocytic leukemia. The myeloid cell lines HL-60, K562, KG-1, and U937 were all reactive with PM-81. The lymphoid lines CCRF-CEM and Daudi did not express PM-81 but HSB-2 was positive. The PM-81 antigen was absent on myeloid and erythroid progenitor cells as determined by their insusceptibility to complement-dependent lysis. In addition, only PM-81-unreactive cells were capable of colony formation. Furthermore, the PM-81 antibody does not appear to induce modulation of the antigen to which it binds. Thus, this monoclonal antibody appears to fulfill several criteria for clinical utility in the diagnosis and treatment of both acute myelocytic and acute lymphocytic leukemia.
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PMID:A unique antigen expressed on myeloid cells and acute leukemia blast cells defined by a monoclonal antibody. 657 89

We examined the synthesis of lactoferrin, an iron binding protein that, among hematopoietic cells, is restricted to secondary granules of polymorphonuclear leukocytes. Lactoferrin biosynthesis was absent from leukemic myeloblasts and promyelocytes but abundant in normal bone marrow and both the bone marrow and peripheral blood of patients with chronic myelogenous leukemia (CGL) if the samples contained substantial numbers of myelocytes and metamyelocytes. Lactoferrin was present in the steady state in normal or CGL bands and polymorphonuclear leukocytes, but no lactoferrin biosynthesis was detectable in these samples. Taken together, these results suggest that lactoferrin accumulation begins with the onset of biosynthesis at the myelocyte stage and is largely complete by the beginning of the band stage of maturation. HL-60 cells, a permanent promyelocytic leukemia cell line, synthesized no lactoferrin. Translation of messenger RNA in Xenopus laevis oocytes revealed that mRNA from patients with chronic myelogenous leukemia and abundant myelocytes and metamyelocytes directed the synthesis of readily detectable amounts of lactoferrin, whereas HL-60 cells contained no translatable lactoferrin mRNA. We thus hypothesize that lactoferrin is a useful marker of gene expression restricted to the terminal stages of granulocyte maturation. Biosynthesis of this protein appears to be mediated by appearance of translatable mRNA at the myelocyte stage, coincident with development of secondary granules. Absence of lactoferrin production by HL-60 cells is due to absence of translatable lactoferrin mRNA, either because of lineage infidelity of these transformed cells or because of arrest before the developmental stage at which secondary granules appear.
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PMID:Lactoferrin biosynthesis during granulocytopoiesis. 659


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