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

Anti-SSEA-1 which binds to glycoconjugates with a Gal beta 1-4(fuc alpha 1-3)GlcNAc epitope and VIM-2 which binds to gangliosides with a NeuAc alpha 2-3GlcNAc beta-4(FUC alpha 1-3) GlcNAc beta 1-3Gal-epitope were used to determine the expression of their corresponding carbohydrate antigens in human leukocytes and leukemia cells. Expression of these antigens was evaluated by immunohistochemical staining of plastic embedded sections of bone marrow or isolated cells, and by immunostaining of isolated glycosphingolipids separated by thin layer chromatography. The expression of both antigens was restricted to normal and leukemic myeloid cells. A range of positive immunohistochemical staining was found among normal marrow myeloid precursors, with myeloblasts giving weaker staining than more mature cells (promyelocytes, myelocytes, metamyelocytes). A similar trend was observed with leukemia cell lines, in that the myeloblastic cell line KG1 was weakly stained compared to the partially differentiated cell line HL-60. Immunohistochemical staining of marrows from acute leukemia patients showed that the VIM-2 antigen is more strongly expressed than the SSEA-1 antigen. Interestingly, both antibodies stained AMMoL cells more intensely than AML cells. Granulocytes from marrows of chronic myelogenous leukemia (CML) patients were intensely stained by both antibodies, whereas lymphocytic leukemias (acute lymphocytic, chronic lymphocytic and hairy cell marrows) were negative. Thus, although both antigens are restricted to myeloid cells there are differences in the level of expression depending on the level of cell maturity. Immunostaining of glycosphingolipids isolated from myeloid cells demonstrated that the SSEA-1 epitope is carried by several neutral glycosphingolipids and that the VIM-2 epitope is carried by three or more gangliosides. Major SSEA-1 glycosphingolipids, with seven to more than ten monosaccharides, are expressed by all myeloid cells regardless of the level of maturity, although quantitative differences are apparent in different patient samples. Two strongly immunoreactive VIM-2 gangliosides with ten and twelve monosaccharides, respectively were found in myeloid cells. The ratio of these two gangliosides varied dramatically, with greater amounts of the more complex ganglioside being present in most cell samples. Normal neutrophils and CML cells had much greater quantities of the VIM-2 gangliosides than acute leukemia cells. This observation correlates with our earlier findings that: (1) acute leukemia cells have less total ganglioside than granulocytes and (2) acute leukemia cells have a predominance of short chain gangliosides (i.e. less than five monosaccharide units). Finally, both CML cells and normal neutrophils express a shorter chain VIM-2 ganglioside, which was not detected in acute myelogenous leukemia cells.
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PMID:Distribution of VIM-2 and SSEA-1 glycoconjugate epitopes among human leukocytes and leukemia cells. 169 Mar 17

We have studied the biosynthesis of altered O-glycan structures on leukocytes from patients with chronic myelogenous leukemia and with acute myeloblastic leukemia (AML). It has been shown previously that the activity of CMP-NeuAc:Gal beta 1-3GalNAc alpha-R (sialic acid to galactose) alpha(2-3)-sialytransferase (EC 2.4.99.4) is increased in leukocytes from patients with chronic myelogenous leukemia (M. A. Baker, A. Kanani, I. Brockhausen, H. Schachter, A. Hindenburg, and R. N. Taub, Cancer Res., 47: 2763-2766, 1987) and with AML (A. Kanani, D. R. Sutherland, E. Fibach, K. L. Matta, A. Hindenburg, I. Brockhausen, W. Kuhns, R. N. Taub, D. van den Eijnden and M. A. Baker, Cancer Res., 50: 5003-5007, 1990). This increased activity may in part be responsible for the hypersialylation observed in leukemic leukocytes; however, hypersialylation may also be due to changes in underlying O-glycan structures. To test this hypothesis, we have assayed in normal human granulocytes and leukemic leukocytes several glycosyltransferases involved in the synthesis and elongation of the four common O-glycan cores. UDP-GlcNAc:Gal beta 1-3GalNAc-R (GlcNAc to GalNAc) beta(1-6)-GlcNAc transferase (EC 2.4.1.102), which synthesizes O-glycan core 2 (GlcNAc beta 1-6[Gal beta 1-3]GalNAc alpha), is significantly elevated in chronic myelogenous leukemia (4-fold) and AML (18-fold) leukocytes relative to normal human granulocytes. Neither normal nor leukemic cells show detectable activities of GlcNAc transferases which synthesize O-glycan core 3 (GlcNAc beta 1-3GalNAc-R) and core 4 (GlcNAc beta 1-6[GlcNAc beta 1-3] GalNAc-R) or the blood group I structure. The beta 3-GlcNAc transferase which elongates core 1 and core 2 was found at low levels in normal granulocytes but was not detectable in leukemic cells. The beta 3-GlcNAc transferase and beta 4-Gal transferase involved in poly-N-acetyllactosamine synthesis, as well as the beta 3-Gal transferase synthesizing core 1 (Gal beta 3 GalNAc), were present in all samples but were significantly increased in patients with AML. The observed changes are consistent with hypersialylation in leukemia.
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PMID:Biosynthesis of O-glycans in leukocytes from normal donors and from patients with leukemia: increase in O-glycan core 2 UDP-GlcNAc:Gal beta 3 GalNAc alpha-R (GlcNAc to GalNAc) beta(1-6)-N-acetylglucosaminyltransferase in leukemic cells. 199 66

We have examined the role of CMP-NeuAc:Gal beta 1-3GalNAc-R alpha(2-3)-sialyltransferase in fresh leukemia cells and leukemia-derived cell lines. Enzyme activity in normal granulocytes using Gal beta 1-3GalNAc alpha-o-nitrophenyl as substrate was 1.5 +/- 0.7 nmol/mg/h whereas activity in morphologically mature granulocytes from 6 patients with chronic myelogenous leukemia (CML) was 4.2 +/- 1.6 nmol/mg/h (P less than 0.05). Myeloblasts from 5 patients with CML in blast crisis showed enzyme activity levels of 6.5 +/- 2.5 nmol/mg/h. From 2 patients with CML, both blasts and granulocytes were obtained, with higher enzyme activity in the patients' blasts (7.1 nmol/mg/h) than in their granulocytes (4.9 nmol/mg/h) in both cases, suggesting that the increase in enzyme activity is related to the differentiation or proliferation status of the CML cells. However, similarly high enzyme levels were also seen in myeloblasts from acute myeloblastic leukemia patients (5.6 +/- 1.4 nmol/mg/h) and in some acute myeloblastic leukemia-derived cell lines (KG1a and HL60), suggesting that increased levels of this enzyme are not directly correlated with the presence of the Ph1 chromosome. This alpha(2-3)-sialyltransferase activity can also be detected in normal peripheral blood lymphocytes and exhibits increased activity in chronic lymphocytic leukemia cells and acute lymphoblastic leukemia. These data suggest that the level of enzyme activity may vary with growth rate and maturation status in myeloid and lymphoid hemopoietic cells. Finally, we have identified a glycoprotein in acute myeloblastic leukemia cells that serves as a substrate for the alpha(2-3)-sialyltransferase. The desialylated form of the glycoprotein was resialylated in vitro by the purified placental form of this alpha(2-3)-sialyltransferase and exhibits a molecular weight of about 150,000.
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PMID:Human leukemic myeloblasts and myeloblastoid cells contain the enzyme cytidine 5'-monophosphate-N-acetylneuraminic acid:Gal beta 1-3GalNAc alpha (2-3)-sialyltransferase. 237 65

Six monoclonal antibodies with known specificities for the carbohydrate antigens i, X or Y, and seven anti-myeloid antibodies (determinants unknown) selected for their differing reaction patterns with human leucocytes were tested in chromatogram binding assays for reactions with myeloid cell glycolipids derived from normal human granulocytes and chronic myelogenous leukemia cells. Antigenicities were found exclusively on minor glycolipids which were barely or not at all detectable with orcinol-sulphuric acid stain. Among these, a neutral glycosphingolipid bound the anti-i antibody Den and chromatographed as the ceramide octasaccharide, Gal beta 1----4GlcNac beta 1----3Gal beta 1----4GlcNac beta 1----3Gal beta 1----4GlcNAc beta 1----3Gal beta 1----4Glc-Cer. Several species of neutral glycosphingolipids with six to more than ten monosaccharides were detected which carry the X antigen and others the Y antigen: Gal beta 1----4(Fuc alpha 1----3)GlcNAc and Fuc alpha 1----2Gal beta 1----4(Fuc alpha 1----3)GlcNAc, respectively. In addition, three new types of carbohydrate specificities were detected among the myeloid cell glycolipids. Two were associated with neutral glycolipids: the first, recognised by anti-myeloid antibodies VIM-1 and VIM-10, was expressed on a distinct set of glycolipids with six or more monosaccharides, and the second, recognized by VIM-8, was expressed on glycolipids with more than ten monosaccharides. The third specificity, recognised by the anti-myeloid antibody VIM-2, was expressed on slow migrating sialoglycolipids with backbone structures of the poly-N-acetyllactosamine type that are susceptible to degradation with endo-beta-galactosidase. Thus, we conclude that the i and Y antigens occur among the glycolipids of normal myeloid and chronic myelogenous leukemia cells and that a high proportion of hybridoma antibodies raised against differentiation antigens of myeloid cells are directed at carbohydrate structures.
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PMID:Glycosphingolipid carriers of carbohydrate antigens of human myeloid cells recognized by monoclonal antibodies. 241 35

Granulocytes from patients with chronic myelogenous leukemia (CML) are morphologically identical to their normal counterparts but show marked differences in circulation patterns and in some membrane properties. We have previously shown that there is abnormal lectin binding to CML granulocytes, and aberrant sialylation of membrane glycoproteins. To examine the changes in sialylation of CML granulocytes further, we have studied membrane preparations from CML and normal granulocytes for specific sialyltransferase activity. Because sialyltransferase enzymes are specific for the configuration of the acceptor group, enzyme activity was assayed by measuring transfer of sialic acid from CMP-14C-sialic acid to substrates of defined structure. As compared with those of normal counterparts, CML extracts catalyzed a 50% higher overall rate of sialylation of asialofetuin, a substrate possessing both N- and O-linked acceptors. Studies of enzyme specificity utilizing porcine and ovine submaxillary mucins, antifreeze glycoprotein and alpha-1 acid glycoprotein as acceptors showed that the increased sialylation by CML extracts was due primarily to substrates with the O-linked Gal beta 1----3GaINAc acceptor group. These data suggest that sialyltransferase activity is increased in CML granulocytes compared to normal granulocytes and that the increased enzyme activity is specific for O-linked Gal beta 1----3GaINAc. This enzyme activity may be directly responsible for the abnormal membrane sialylation and pathophysiological behavior of these cells.
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PMID:Increased activity of a specific sialyltransferase in chronic myelogenous leukemia. 241 27

A novel sialylated fucosyl glycolipid, which is present at an elevated level in chronic myelogenous leukemia cells, was isolated. The structure of this fucoganglioside was elucidated by methylation analysis, fast atom bombardment-mass spectrometry, and enzymatic degradation, followed by reaction with anti-Lex, Gal beta 1----4 (Fuc alpha 1----3) GlcNAc beta 1----, monoclonal antibody. The structure of this ganglioside was found to be: (Formula: see text). This structure is unique in that a fucose is attached to the internal N-acetylglucosamine but not to the subterminal N-acetylglucosamine. Since this glycolipid is apparently absent in normal granulocytes or acute myelogenous leukemia cells, it can be a specific marker for chronic myelogenous leukemia cells. Based on the structures of this fucoganglioside and normal granulocyte glycolipids, a biosynthetic pathway of extension, sialylation, followed by fucosylation is proposed.
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PMID:Structure of a novel sialylated fucosyl lacto-N-norhexaosylceramide isolated from chronic myelogenous leukemia cells. 345 27

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

Gangliosides isolated from the cells of three patients with chronic myelogenous leukemia (CML) were purified by Folch partitioning, diethylaminoethyl Sephadex, Florisil (acetylated gangliosides), and silicic acid chromatography and were structurally analyzed using thin-layer and gas-liquid chromatography, methylation analysis, enzyme degradation, and high-performance liquid chromatography. With these methods, the major gangliosides isolated were II3-alpha-N-acetylneuraminosyl-lactosylceramide, IV3-alpha-N-acetylneuraminosyl-neolactotetraosylceramide (sialosylparagloboside), and a ganglioside with the following structure: NeuAc alpha 2 leads to 3(Gal beta 1 leads to 4 GlcNac beta 1 leads to 3)2Gal beta 1 leads to 4Glc beta 1 leads to 1Cer. This ganglioside has previously been characterized as an "i" active compound. Like normal neutrophils, CML cells contain monosialogangliosides that belong to the lactosyl and neolacto family. However, our study shows that CML cells differed from normal neutrophils in that they contained less total ganglioside, and their major ganglioside species is II3-alpha-N-acetylneuraminosyl-lactosylceramide. Differences between gangliosides of CML and acute nonlymphoblastic leukemias are discussed.
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PMID:Isolation and characterization of gangliosides from chronic myelogenous leukemia cells. 658 65

Particulate membrane preparations from K-562 [human CML (chronic-myelogenous-leukaemia)-derived] cells catalyse the transfer of [3H]galactose from UDP-[3H]-galactose and [3H]N-acetylglucosamine from UDP-[3H]N-acetylglucosamine into an endogenous product that on digestion with Pronase yields long-chain glycopeptides (mol.wt. 7000--10 000) called 'erythroglycan'. Incorporation of either labelled sugar increased up to 60 min of incubation time. The labelled erythroglycan was isolated by chromatography on Sephadex G-50 and characterized by digestion with endo-beta-galactosidase from Escherichia freundii, followed by analysis on Bio-Gel P-2 and paper chromatography. This digestion gave the following four products: (1) a disaccharide with the sequence beta GlcNAc-beta Gal; (2) a trisaccharide with the sequence betaGal-betaGlcNAc-beta Gal; (3) a larger oligosaccharide containing galactose and N-acetylglucosamine; and (4) a putative protein-linkage region.
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PMID:Cell-free biosynthesis of erythroglycan in a microsomal fraction from K-562 cells. 679 62

Human neutrophils and lymphocytes have been shown to have different classes of neutral glycolipids. We have investigated alterations of glycolipids in the human myeloid leukemias to see how their neutral glycolipids differ from those of normal neutrophils. The chemical structures of the neutral glycolipids from large numbers of homogeneously purified leukemia cells were determined using column and thin-layer chromatography, gas-liquid chromatography (GLC), GLC-mass spectrometry, and direct probe mass spectrometry. Our results showed that cells from patients with acute myelogenous leukemia (AML) had less than half the amount of neutral glycolipid per cell than did cells from patients with chronic myelogenous leukemia (CML). Chromatographic mapping of the neutral glycolipids from these cells showed that AML cells had less of the polar, long-chain neutral glycolipids than did CML cells. The studies confirmed that over 99% of the neutral glycolipids were contained in a population of compounds with 1, 2, 3, and 4 sugar-containing neutral glycolipids whose structures are: Glc 1 --> 1 ceramide; Gal 1 --> 1 ceramide; Gal 1 --> 4 Glc 1 --> 1 ceramide; Gal 1 --> 4 Gal 1 --> 1 ceramide; GlcNAc 1 --> 3 Gal 1 --> 4 Glc 1 --> 1 ceramide; and Gal 1 --> 4 GlcNAc 1 --> 3 Gal 1 --> 4 Glc 1 --> 1 ceramide. Lactosyl ceramide was the major glycolipid in both AML and CML cells. The studies show that human myeloid leukemia cells have the same neutral glycolipids as normal neutrophils. The alterations in neutral glycolipid distribution in leukemia suggest that they might be useful as "differentiation markers", with the morphologically more "mature" leukemias having more complex glycolipids. We were unable to detect novel or "malignancy-associated" neutral glycolipids in any of the leukemias we studied.-Klock, J. C., J. L. D'Angona, and B. A. Macher. Chemical characterization of neutral glycolipids in the human myeloid leukemias.
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PMID:Chemical characterization of neutral glycolipids in the human myeloid leukemias. 694 77


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