Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We have investigated the configuration of immunoglobulin (Ig) genes in leukaemic cells in 17 patients with B-cell leukaemias (11 chronic lymphocytic leukaemias (B-CLL); 4 prolymphocytic leukaemias (B-PLL), and two hairy cell leukaemias (HCL)). In addition we studied four patients with T chronic lymphocytic leukaemia (T-CLL); four patients with acute leukaemia (3 acute lymphoblastic leukaemias (ALL), and 1 mixed acute leukaemia (M.AL)); and six patients with chronic granulocytic leukaemias in blastic crisis (CGL.BC). The heavy chain genes (H) were analysed by using probes for the constant region of the mu chains (C mu) and for the joining region (JH). The light chain genes were analysed by using probes for the constant region of the kappa (C kappa) and lambda (C lambda) chains. We have found rearranged Ig genes in all cases of B-CLL, B-PLL and HCL, but in none of the patients with T-CLL. In one case of HCL, both mu genes were deleted, indicating that in this case the class switch has taken place. In four out of six cases with either ALL or lymphoid CGL.BC and in one case of M.AL, an Ig gene rearrangement was also found. No rearrangement was detected in two cases of myeloid CGL.BC. When the combination of rearrangement versus germ-line configuration was considered, a variety of patterns emerge, but in no case did we find a L chain gene rearranged without at least one H chain gene being rearranged as well. Whereas in the majority of cases of B-CLL only one H chain gene is rearranged, in nearly all cases of B-PLL both H chain genes are rearranged. By systematic analysis of restriction fragment sizes of rearranged genes, we have established that a large number of different variable regions for the H chain (VH) are involved in Ig gene rearrangement in B-cell malignancies. Our data confirm that testing for Ig gene rearrangement may be the most sensitive and specific test for identifying leukaemic cells of B lineage.
Mol Biol Med 1984 Feb
PMID:DNA rearrangements of immunoglobulin genes correlate with phenotypic markers in B-cell malignancies. 643 75

Monoclonal antibodies generated against normal and leukemic human leukocytes were tested for their differential reactivity with leukemia and lymphoma cell lines as well as with circulating lymphoid and myeloid leukemic cells by means of immuno-scanning electron microscopy (immuno-SEM). Anti-T (OKT3), anti-mu-chain, anti-CALLA (J5), anti-BA-1, anti-BA-2, and anti-nonlymphoid (Mol) monoclonal antibodies were covalently conjugated to polystyrene latex microspheres (immunolatex), using a two-step glutaraldehyde reaction, and subsequently incubated with the various cell types. Cultured B-type Burkitt lymphoma cells (Daudi) and chronic lymphocytic leukemia (CLL) cells displayed extensive labeling with monoclonal anti-mu, anti-B1, and anti-BA-1 immunolatex conjugates, while cultured malignant T cells (HD-Mar) showed positive labeling with OKT3 immunolatex alone. Cultured myelomonocytic cells (GDM-1) and cells obtained from patients with acute myeloblastic (AML) and monoblastic leukemia (AMoL) labeled only with anti-Mol immunolatex, while cultured promyelocytic cells (HL-60) displayed far less labeling with this conjugate. Common-type acute lymphoblastic leukemia (C/ALL) cells were labeled predominantly with the J5 (anti-CALLA) and anti-BA-2 immunolatex conjugates. Evidence is presented indicating that immuno-SEM employing monoclonal antibodies is a reproducible technique which may be used in the study of leukocyte maturation and may provide additional information in the classification of poorly differentiated leukemias.
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PMID:Utilization of monoclonal antibodies and immuno-scanning electron microscopy for the positive identification of human leukemic cells. 658 Nov 72

The biantennary N-acetyllactosamine type oligosaccharide is attached to asparagine-297 of the human IgG heavy chain, which is an integral part of the tertiary structure of the Fc region, and is quite important in the role of IgG. Pyridylamination and analysis by HPLC can be performed more rapidly and simply than conventional carbohydrate analysis. We applied it to the analysis of the oligosaccharide structures of IgG from the serum of patients with leukemia, CLL and AML. The proportion of oligosaccharide from leukemia patients with a bisecting N-acetylglucosamine residue was almost equal to that of healthy individuals. However, the proportion of fucose and galactose residues differed. These data suggest that the analysis of the fucose and the terminal galactose residue of such oligosaccharides will be useful in the classification of leukemia.
Biochem Mol Biol Int 1994 Apr
PMID:Analysis of oligosaccharides of human IgG from serum of leukemia patients. 806 39

BCL3 is a candidate proto-oncogene involved in the recurring translocation t(14;19) found in some patients with chronic lymphocytic leukemia. BCL3 protein acts as an I kappa B in that it can specifically inhibit the DNA binding of NF-kappa B factors. Here, we demonstrate that BCL3 is predominantly a nuclear protein and provide evidence that its N terminus is necessary to direct the protein into the nucleus. In contrast to I kappa B alpha (MAD3), BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm; instead, in cotransfection assays, it alters the subnuclear localization of p50. The two proteins colocalize, suggesting that they interact in vivo. Further immunofluorescence experiments showed that a mutant p50, lacking a nuclear localization signal and restricted to the cytoplasm, is brought into the nucleus in the presence of BCL3. Correspondingly, a wild-type p50 directs into the nucleus a truncated BCL3, which, when transfected alone, is found in the cytoplasm. We tested whether BCL3 could overcome the cytoplasmic retention of p50 by I kappa B alpha. Results from triple cotransfection experiments with BCL3, I kappa B alpha, and p50 implied that BCL3 can successfully compete with I kappa B alpha and bring p50 into the nucleus; thus, localization of NF-kappa B factors may be affected by differential expression of I kappa B proteins. These novel properties of BCL3 protein further establish BCL3 as a distinctive member of the I kappa B family.
Mol Cell Biol 1994 Jun
PMID:BCL3 encodes a nuclear protein which can alter the subcellular location of NF-kappa B proteins. 819 32

Bacteriophage P22 and lambda are related bacteriophages with similar gene organizations. In lambda the cll-dependent Pl promoter is responsible for lambda int gene expression. The only apparent counterpart to pl in P22 is oriented in the opposite direction, and cannot transcribe the P22 int gene. We show that this promoter, called P(al), is active both in vivo and in vitro, and is dependent upon the P22 cll-like gene, called c1. We have also determined the DNA sequence of a 3.3 kb segment that closes the gap between previously reported sequences to give a continuous sequence between the P22 pL promoter and the int gene. The newly determined sequence is densely packed with genes from the pL direction, and the proteins predicted by the sequence show excellent correlation with the proteins mapped by Youderian and Susskind in 1980. However, the sequence contains no apparent genes in the opposite (p(al)) direction, and no additional binding motifs for the P22 c1 protein. We conclude that int gene expression in P22 is regulated by a different mechanism than in lambda.
Mol Microbiol 1993 Jul
PMID:The int genes of bacteriophages P22 and lambda are regulated by different mechanisms. 841 79

Nucleotide excision repair (NER) activity was investigated in lymphocytes from patients with chronic lymphocytic leukemia (CLL). The NER process consists of two broad stages: incision/excision of the damaged oligonucleotide and resynthesis of the repair patch. NER in CLL lymphocytes was monitored with the use of in vitro biochemical assays, allowing the determination of either the extent of repair synthesis or the incision activity on damaged plasmid DNA during incubation with whole-cell protein extracts. Fresh CLL tumor cells were purified from the blood of 7 untreated patients and 11 patients who had been treated with chemotherapy. No repair activity was found in 14 extracts (7 treated and 7 untreated) or in normal blood peripheral lymphocytes. The defect was at the level of both repair synthesis and incision/excision activity of DNA damage. In contrast, 4 of the extracts exhibited 25-60% of the repair activity measured in an extract from a control repair-proficient cell line. A linear relationship was found between the values of DNA-repair synthesis and incision activities, which indicates that the extent of significant incision was the limiting factor in these protein extracts. All of the extracts that exhibited DNA-repair activity were purified from lymphocytes of treated patients. These data suggest that chemotherapy might exert an effect on the status of repair activity in the lymphoid tumor cells of patients.
Mol Pharmacol 1996 May
PMID:DNA repair activity in protein extracts of fresh human malignant lymphoid cells. 862 24

HflB, also called FtsH, is an essential Escherichia coli protein involved in the proteolysis of the heat-shock regulator sigma 32 and of the phage regulator lambda cll. The hflB1(Ts) allele (formerly called ftsH1) conferring temperature-sensitive growth at 42 degrees C is suppressed by loss of the ferric-uptake repressor Fur and by anaerobic growth. We show here that suppression requires TonB-dependent Fe(III) transport in the hflB1(Ts) fur mutant during aerobic growth at 42 degrees C and Feo-dependent Fe(II) transport during anaerobic growth at 42 degrees C. Temperature-resistant growth of hflB1(Ts) strains is also observed at 42 degrees C in the presence of a high concentration of Fe(II), Ni(II), Mn(II) or Co(II) salts, but not in the presence of Zn(II), Cd(II), Cu(II), Mg(II), Ca(II) or Cr(III) salts. However, neither Ni(II) nor a fur mutation permits growth in the complete absence of HflB. The heat-shock response, evaluated by an htpG::lacZ fusion, is overinduced in hflB1(Ts) strains at 42 degrees C because of stabilization of sigma 32. Growth in the presence of Ni(II) or in the absence of the Fur repressor abolishes this overinduction in the hflB1(Ts) strain, and, in the hflB1(Ts) fur mutant, sigma 32 is no longer stabilized at 42 degrees C. These results reinforce the recent observation that HflB is a metalloprotease active against sigma 32 in vitro and suggest that it can associate functionally in vivo with Fe(II), Ni(II), Mn(II) and Co(II) ions.
Mol Microbiol 1995 Oct
PMID:Regulation of the heat-shock response depends on divalent metal ions in an hflB mutant of Escherichia coli. 870 44

The treatment of chronic lymphocytic leukemia includes the use of alkylating agents, steroids, and more recently nucleoside analogues. While prior studies have described potential mechanisms of 2-chlorodeoxyadenosine cytotoxicity including the accumulation of DNA strand breaks and induction of apoptosis or programmed cell death, the expression of p53 and its downstream target WAF1/CIP1 have not been examined. In this report we describe the induction of p53 and WAF1/CIP1 in the apoptotic chronic lymphocytic leukemia cells after exposure to 2-chlorodeoxyadenosine.
J Mol Med (Berl) 1996 Mar
PMID:The induction of p53 and WAF1/CIP1 in chronic lymphocytic leukemia cells treated with 2-chlorodeoxyadenosine. 884 64

We demonstrated previously that the nucleoside of fludarabine (F-ara-A), a clinically effective agent against chronic lymphocytic leukemia and low-grade lymphoma, produces synergistic cytotoxicity against cisplatin-resistant CP2.0 human colon tumor cells when administered in combination with cisplatin. The purpose of this study was 2-fold: (i) to determine whether the synergy occurs in K562 human chronic myelogenous leukemia cells, which, unlike CP2.0 cells, are relatively resistant to drug-induced apoptosis because they express P210(bcr-abl) and (ii) to study the underlying mechanism for the synergy if the enhancement of cytotoxicity occurs in K562 cells. When K562 cells were treated with fludarabine nucleoside and cisplatin as single agents for 4 hr, IC50 values for fludarabine and cisplatin were 3.33 and 2.28 microM, respectively, as measured by a clonogenic survival assay. The simultaneous treatment of K562 cells with the two agents resulted in synergistic cell killing as determined by median-effect analysis. Such synergistic cell killing by combined cisplatin and fludarabine could not be detected in repair-deficient human xeroderma pigmentosum cell lines. Within the range of cytotoxic concentrations, fludarabine (2.5-15 microM) and cisplatin (3-30 microM) as single agents produced no detectable internucleosomal DNA fragmentation as revealed by gel electrophoresis, nor did the combination of the two drugs induce apoptotic DNA degradation. The effects of fludarabine on the repair of cisplatin-induced DNA adducts and interstrand cross-links in K562 cells were analyzed to determine their correlation with the cytotoxic synergy. The interstrand cross-links were measured by the ethidium bromide binding fluorescence assay and quantitative Southern blotting technique. Repair of the intrastrand adducts was detected with whole-cell extracts using a cisplatin-damaged plasmid as the substrate for the in vitro repair assay. Fludarabine at clinically achievable concentrations (1.5-4.5 microM fludarabine nucleoside; 20-100 microM fludarabine triphosphate) inhibited the repair of the DNA lesions induced by cisplatin in a dose-dependent fashion in K562 cells but not in xeroderma pigmentosum cells. Cotreatment with fludarabine preferentially increased the number of interstrand cross-links induced by cisplatin in actively transcribed genes in K562 cells. These data demonstrate the DNA-repair-inhibitory effect of fludarabine and suggest that this effect may contribute to the synergistic cytotoxicity of the fludarabine/cisplatin combination that resulted in decreased clonogenic survival of apoptosis-resistant K562 cells.
Mol Pharmacol 1997 Nov
PMID:Fludarabine-mediated repair inhibition of cisplatin-induced DNA lesions in human chronic myelogenous leukemia-blast crisis K562 cells: induction of synergistic cytotoxicity independent of reversal of apoptosis resistance. 935 70

Alleles of the IL-1 genes are associated with several autoimmune and inflammatory diseases, where they tend to have a role in the severity of the disease rather than in susceptibility to the disease itself. Allele 2 of the variable number tandem repeat (VNTR) polymorphism in the IL-1 receptor antagonist (IL-1ra) gene was the first marker of the IL-1 cluster to be associated in this way with severity of chronic, systemic and local inflammatory diseases. Because of the role that IL-1 also plays in the pathobiology of certain hematopoietic disorders, we aimed at examining the allelic distribution of the IL-1ra VNTR in leukemias, lymphomas and related malignancies. While in patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), multiple myeloma (MM) and related disorders, primary acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and Hodgkin's disease (HD), the allelic distribution of IL-1RN was comparable to that seen in healthy control subjects, in a small group of patients with secondary AML the frequency of the IL-1RN*4 allele appeared to be significantly increased.
Cytokines Mol Ther 1996 Dec
PMID:Polymorphism within the second intron of the IL-1 receptor antagonist gene in patients with hematopoietic malignancies. 938 10


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