Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the activity and transcription of UDP-N-acetylglucosamine: beta-D-mannoside beta-1,4-N-acetylglucosaminyl-transferase III (GnT-III: EC 2.4.1.144) were investigated in haematological malignancies. GnT-III activity was elevated in patients with chronic myelogeneous leukaemia in blast crisis (CML-BC) and patients with multiple myeloma (MM); whereas most of the normal healthy subjects and patients with other haematological malignancies, including CML in its chronic phase, showed negligible activity. The GnT-III transcript of leukaemic cells from various haematological diseases showed a single band with a similar size. The ratio of GnT-III activity per normalized transcript in CML-BC was considerably higher than in the other conditions, which provided the possibility that in CML-BC the transcript or the enzyme protein might be more stable, or that a post-translational modification of the enzyme might enhance its activity. Furthermore, a lectin blot analysis of patient specimens and a lectin fluorescence study of CML cell lines revealed that E4-PHA binding to surface glycoproteins correlated with GnT-III activity, indicating that more bisecting GlcNAc was added to these glycoproteins, catalysed by elevated GnT-III in CML-BC.
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PMID:Changes of beta-1,4-N-acetylglucosaminyltransferase III (GnT-III) in patients with leukaemia. 749 37

N-acetylglucosaminyltransferase III (GlcNAc-TIII), a product of the human MGAT3 gene, was discovered as a glycosyltransferase activity in hen oviduct. GlcNAc-TIII transfers GlcNAc in beta4-linkage to the core Man of complex or hybrid N-glycans, and thereby alters not only the composition, but also the conformation of the N-glycan. The dramatic consequences of the addition of this bisecting GlcNAc residue are reflected in the altered binding of lectins that recognize Gal residues on N-glycans. Changes in GlcNAc-TIII expression correlate with hepatoma and leukemia in rodents and humans, and the bisecting GlcNAc on Asn 297 of human IgG antibodies enhances their effector functions. Overexpression of a cDNA encoding GlcNAc-TIII alters growth control and cell-cell interactions in cultured cells, and in transgenic mice. While mice lacking GlcNAc-TIII are viable and fertile, they exhibit retarded progression of diethylnitrosamine (DEN)-induced liver tumors. Further biological functions of GlcNAc-TIII are expected to be uncovered as mice with a null mutation in the Mgat3 gene are challenged.
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PMID:Biological consequences of overexpressing or eliminating N-acetylglucosaminyltransferase-TIII in the mouse. 1241 19

Reduction of pig cell-surface alpha-galactosyl (Gal) epitope, Galalpha1, 3Galbeta1, 4GlcNAc-R, by the introduction of glycosyltransferase genes is effective in suppressing hyperacute rejection (HAR) in pig-to-human xenotransplantation. The transmission of porcine endogenous retroviruses (PERVs) has been recognized as a potential risk factor associated with xenotransplantation. In this study, effects of the introduction of glycosyltransferase genes to pig cells on the sensitivity of gammaretroviruses to human serum were investigated. Pig endothelial cells (PEC), PEC transduced with alpha1,2 fucosyltransferase (FT), alpha2,3 sialyltransferase (ST), or N-acetylglucosaminyltransferase III (GnT-III), and human embryonic kidney (HEK) 293 cells were transduced with the LacZ gene with the packaging signal of murine leukemia virus (MuLV) under the control of the long terminal repeat of MuLV by a pseudotype infection. Then, the cells were further infected with PERV subtype B (PERV-B) or feline leukemia virus subgroup B (FeLV-B). Culture supernatants of the infected cells were mixed with human serum (HS) and then inoculated to HEK293 cells. The inoculated cells were histochemically stained and lacZ-positive blue foci were counted. Glycosyltransferase activity, xenoantigenicity, and alpha-Gal epitope density in the cells were measured at the time of the infection experiments. PERV-B or FeLV-B particles from the parental PEC were efficiently neutralized by HS, while those from PEC transduced with alpha1,2FT, alpha2,3ST or GnT-III were less sensitive to HS. The transduced PEC exhibited high levels of activity of the introduced glycotransferases, and expressed fewer xenoantigens and cell-surface alpha-Gal epitopes. Our results suggest that gammaretroviruses including PERVs produced by transgenic pigs, that are generally modified to reduce the cell-surface alpha-Gal epitope to overcome the HAR in xenotransplantation, are less sensitive to HS.
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PMID:Sensitivity to human serum of gammaretroviruses produced from pig endothelial cells transduced with glycosyltransferase genes. 1470 22

To investigate the influence of N-linked oligosaccharides at asparagines-297 on the cytolytic potential of chimeric CD19 antibodies, three distinct variants were generated by production in different expression systems. The same chimeric CD19 antibody was produced in Sf21 insect cells, human 293 T cells, and 293 T cells expressing a co-transfected beta1,4-N-acetylglucosaminyltransferase III (GnTIII). The N-glycan structures and the cytolytic potential of the antibodies produced in these three systems were directly compared. After expression in insect cells, the antibody carried paucimannosidic N-linked oligosaccharides, distinct from the complex biantennary carbohydrate moieties attached to the product from human cells. After co-expression with GnTIII in human cells, the antibody carried an eightfold greater percentage of oligosaccharides with a bisecting N-acetylglucosamine (78.7% versus 9.6%) and a 30-fold increased proportion of bisecting, defucosylated oligosaccharides (15.9% versus 0.5%). The insect cell product triggered stronger antibody-dependent cellular cytotoxicity (ADCC) of a human leukemia-derived cell line than the product from non-re-engineered 293 T cells and was equally effective at 50- to 100-fold lower concentrations. The antibody from glyco-engineered 293 T cells had comparable lytic activity as the insect cell product. Both mediated significant ADCC at lower effector-to-target cell ratios than the antibody from non-re-engineered 293 T cells, and both were highly effective against primary blasts from pediatric leukemia patients. The data demonstrate the influence of the N-glycosylation pattern on the ADCC activity of chimeric CD19 antibodies and point to the importance of suitable expression systems for the production of highly active therapeutic antibodies.
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PMID:Influence of variable N-glycosylation on the cytolytic potential of chimeric CD19 antibodies. 1653 13