Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper we report the structural basis for the nonexpression of G1m(3) and Km (1,2) allotypes in an IgG1 (kappa) human myeloma protein (protein LEC). Heavy and light chains spontaneously dissociate in sodium dodecyl sulfate polyacrylamide gels. Light chains appear to be covalently S-S bonded. Analysis of cysteine-containing peptides shows that the heavy chain of the IgG protein LEC has a deletion of residues 216-230, thus encompassing the entire hinge region. An arginine residue, characteristic of the G1m(3) marker is present at position 214. An alanine at position 153 and a leucine at position 191 of the light chain, characteristic of the Km (1, 2) allotypes, are present. It is likely that the double Km and Gm lack of expression is the result of the deletion. The genetic implications of the sequence of this protein are discussed.
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PMID:Deletion of hinge region of human myeloma IgG1 molecule (protein LEC) associated with nonexpression of G1m (3) and Km (1, 2) allotypes. A possible genetic explanation at the DNA level. 6 77

Five monkeys were treated ip with N-nitrosodiethylamine (DENA), and one was treated with 1-nitrosopiperidine (PIP), starting within 2 months of birth, until hepatocellular carcinoma (HCC) developed. All animals except the PIP-treated monkey had much elevated serum alpha-fetoprotein (AFP) values. Fresh, minced, biopsy-derived tumor was cultured with L-[14C]leucine and L-[14C]lysine. Synthesis of AFP was determined by radioimmunoassay and by specifically precipitable [14C]AFP. Good agreement between these two parameters was obtained for the 4 DENA-induced tumors synthesizing AFP in culture. Tumor from 1 DENA-treated monkey did not synthesize AFP. In addition, neither normal liver nor tumor from the PIP-treated monkey showed AFP synthesis. Rates of synthesis were 0.37-5.50 ng AFP/mg tumor/day, or 0.0012-0.0183 pg AFP/cell/day (if one assumes 3.0 X 10(5) cells/mg tissue) over 48 or 72 hours. Different nodules from the same animal had similar rates of synthesis. For tumors that synthesized AFP in culture, a positive correlation was generally found between rate of synthesis and serum AFP level. The rate of in vitro AFP synthesis observed was lower than that of immunoglobulin synthesis in human myeloma or of AFP synthesis in a rat HCC, but it was close to the estimated rate of AFP synthesis in a monkey HCC line in long-term culture.
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PMID:In vitro alpha-fetoprotein synthesis by monkey hepatocellular carcinoma. 7 69

The amino acid sequence of the heavy-chain variable region of the crystallizable human myeloma protein Dob has been determined. This protein has previously been shown to have a deletion in the hinge region [Lopes, A. D., & Steiner, L. A. (1973) Fed. Proc., Fed. Am. Soc. Exp. Biol. 32, 1003; Steiner, L. A., & Lopes, A. D. (1979) Biochemistry (preceding paper in this issue)]. The complete sequence was established by analysis, in the automated sequenator, of the intact Fd' piece and of three large overlapping fragments prepared from Fd' by digestion with cyanogen bromide, by tryptic digestion of the citraconylated Fd', and by cleavage with hydroxylamine. Portions of the sequence were confirmed by examination of the amino acid composition and the partial sequence of a variety of small peptides obtained by enzymatic degradation. The Dob heavy-chain variable region appears to belong to the VHIII subgroup, but there are several unusual substitutions. Residue 45 in the Dob sequence is proline, although all other known heavy-chain sequences in man, mouse, rabbit, and guinea pig have leucine at this position. Positions 10 (aspartic acid), 68 (alanine), and 82 (leucine) in the Dob sequence are also atypical. There is no deleted segment in the variable region of the Dob heavy chain nor any abnormality in the variable-constant joining region. The hinge-region deletion appears to be the only gross structural anomaly in the Dob heavy chain.
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PMID:Amino acid sequence of the heavy-chain variable region of the crystallizable human myeloma protein Dob. 11 9

Some human marrows in culture release particles with oncornavirus-like properties. This study was designed to examine the immunological properties of similar particles in human marrow culture supernates. Leukemic and nonleukemic marrows were cultured for 5-7 days in the presence of [14C]uridine and [3H]leucine or [3H]glucosamine. Labeled supernatant components banding in sucrose gradient densities of 1.20-1.24 g/ml were used as antigen in a double antibody immunoprecipitation assay. The assay was validated by end point titrations and competition with unlabeled antigen; purified myeloma proteins were used as negative controls. Cross-reactivity with mammalian oncornaviruses, as judged by competitive inhibition of precipitation by these viruses, was slight and at the border of the sensitivity of the method. Precipitated antigens analyzed by SDS polyacrylamide gel electrophoresis contained three distinct polypeptides of about 70,000, 45,000 and 30,000 mol wt; these comigrated with the gp 70, pg 45, and p 30 of a murine leukemia virus. Similar polypeptides were obtained from both leukemic and nonleukemic marrow culture supernates. As determined by the radioimmunoprecipitation assay, 32 of 45 leukemic sera (71%), 36 of 45 normal sera (80%), 15 of 19 sera from family contacts of leukemic patients (79%), 14 of 21 cord blood specimens (67%), and 21 of 23 sera (91%) from patients with systemic lupus erythematosus had detectable antibody activity.
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PMID:Antibodies in human sera to oncorna virus-like proteins from normal or leukemia marrow cell cultures. 18 53

The reactivity of peripheral blood lymphocytes from patients with advanced malignancy was assessed by mitogen-induced stimulation of protein synthesis as measured by 3H-leucine incorporation. It was confirmed that the lymphocyte response of patients was depressed. Furthermore, the lymphocytes of 15 out of 27 cancer patients, selected because of their low responses, inhibited the reactivity of normal lymphocytes in co-cultures. The lymphocytes from one patient with Hodgkin's disease were also inhibitory. In contrast, lymphocytes from healthy subjects, patients with chronic lymphocytic leukaemia, lymphosarcoma or multiple myeloma caused no suppression. Experiments with purified cell populations from patients with carcinoma indicated that purified T cells responded to mitogens while unseparated lymphocytes failed to respond and that the inhibitory activity was due to adherent cells, presumably monocytes. There was no evidence for B-cell-mediated suppression. However, in two cases inhibition was caused by isolated T cells of the patients and not by adherent cells. These experiments suggested that one mechanism for the depression of cell-mediated immunity seen in patients with advanced cancer may be the nonspecific suppresssion of certain T-cell functions by circulating monocytes.
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PMID:Depressed in vitro peripheral blood lymphocyte response to mitogens in cancer patients: the role of suppressor cells. 30 Nov 22

As a means of investigating the immunoglobulin (Ig) deficiency in multiple myeloma, the effects of pokeweed mitogen (PWM) on morphologic transformation and concomitant immunoglobulin synthesis and secretion kinetics were studied in peripheral blood lymphocytes (PBL) of normals and patients with myeloma. Lymphocyte Ig production kinetics, both in the unstimulated state and after five days of culture with PWM, were evaluated by 3H-leucine incorporation. B-lymphocytes were found to be decreased by EC3 rosetting in the myeloma patients studied. In addition their lymphocytes had a mean of 30% transformation compared to 53% for normals (P less than 0.005). After five days of mitogen stimulation in culture, myeloma PBL failed to show the rise in intracellular Ig production seen in normal PBL under similar conditions. Thus, myeloma patients were found to have decreased numbers of EC3 rosetting B-cells, decreased morphologic transformation rate in response to mitogenic stimulation, and failure to increase intracellular Ig after mitogenic stimulation. Possible etiologic mechanisms for the decreased Ig production are discussed.
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PMID:The kinetics of immunoglobulin synthesis by pokeweed mitogen stimulated peripheral blood lymphocytes in multiple myeloma. 31 69

Multiple myeloma is a disease that infrequently involves nonreticuloendothelial tissues and rarely causes pleural effusion. A 59-year-old woman had pleural effusion as the major manifestation of multiple myeloma. Light microscopy of her pleural fluid with Wright stained preparations showed all cells to be bizarre and often multinucleated plasmacytes. Electron microscopy confirmed these results. Intracellular immunofluorescence revealed IgG-kappa immunoglobulin (Ig) in greater than 90% of these cells. Surface immunofluorescence using anti-Ig sera was seen on less than 5% of the pleural fluid cells. 3H leucine incorporation into Ig in vitro was measured for these cells, and secretory curves were obtained that have the typical secretory kinetics of bone marrow plasmacytes. This demonstrates that such cells are viable and are able to synthesize and release immunoglobulin. Treatment of our patient with prednisone, melphalan, and cyclophosphamide resulted in symptomatic improvement and complete resolution of her pleural effusion. Pleural effusion is an unusual but important complication of multiple myeloma and does not necessarily carry the grave prognosis implied in previous reports.
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PMID:Myelomatous pleural effusion: clinical course and immunologic characterization of the pleural fluid cells. 38 84

The biosynthesis and secretion of a glycosylated, K-type immunoglobulin light chain (K-46) was studied in a mouse myeloma tumor, mineral oil plasmacytoma-46B. Viable single cell suspensions were prepared from excised tumors and optimal conditions were established for incorporation of amino acid and carbohydrate precursors into the protein synthesized and secreted by the cells. The glucose analog, 2-deoxy-D-glucose, was utilized as an inhibitor of glycosylation to determine the role of glycosylation in the biosynthesis, intracellular transport, and export of the protein from the cell. It was determined that 6 mM 2-deoxyglucose prevents the incorporation of glucosamine, mannose, and galactose into secreted protein, but permits the incorporation of leucine at approximately 40% of control values. The nonglycosylated protein, secreted in the presence of 2-deoxyglucose, was characterized as a nonglycosylated form of K-46 light chain by the following criteria: (a) electrophoresis in polyacrylamide gels containing sodium dodecyl sulfate, (b) reactivity of the nonglycosylated protein with antisera prepared against native, fully glycosylated, K-46 light chain, (c) analysis of the protein by gel filtration techniques, (d) behavior of the protein on lectin-derivatized Sepharose, and (e) analysis of tryptic peptides derived from the protein. We have concluded that 2-deoxyglucose-inhibited cells synthesize and secrete the normal polypeptide chain of K-46 devoid of its carbohydrate side chain indicating that glycosylation is not an essential step in the biosynthesis, intracellular transport, or export of this protein that is normally synthesized and secreted in a glycosylated form. Under conditions of 2-deoxyglucose inhibition, the nonglycosylated form of K-46 light chain constitutes a significantly greater proportion of accumulated intracellular protein, suggesting that the biosynthesis of the polypeptide chain of K-46 light chain proceeds at a nearly normal rate, but that the absence of the carbohydrate side chain of the protein retards, but does not prevent, the intracellular transport of the protein and its export from the tumor cell.
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PMID:Glycoprotein biosynthesis in myeloma cells. Characterization on nonglycosylated immunoglobulin light chain secreted in presence of 2-deoxy-D-glucose. 40 89

The mRNA coding for the kappa-type constant region (C(kappa)) was purified from two clones derived from the MPC-11 mouse myeloma. This mRNA directs the cell-free synthesis of a C(kappa) precursor (molecular weight, about 15,000) in which an extra piece, 17 residues long, precedes the NH(2)-terminal residue (Ala(109)) of the C(kappa) region. The partial sequence of the extra piece is: Met-X-Thr-Asp-Thr-Leu-Leu-Leu-Trp-Val-Leu-Leu-Leu-Trp-Val-Pro-X- (X is unknown). Met(1) was shown to be the initiator methionine. The sequence of the C(kappa) extra piece is completely different from any known sequence preceding residue Ala(109) in whole light (L) chains, thus establishing that the C(kappa)-region mRNA could not have originated from mRNA coding for the whole L chain. The structural features of the C(kappa) extra piece (marked hydrophobicity, size, and a methionine at the NH(2)-terminus) are identical to those characteristic of the NH(2)-terminal extra piece linked to the variable (V) region of whole L-chain precursors. In addition, the C(kappa) extra piece and the extra piece linked to the V region of MOPC-321 L chain have 70% sequence homology. These findings can be explained by the two genes-one Ig chain hypothesis, if we assume that the DNA coding for the extra piece (xp-DNA) is a constitutive part of the V gene. According to this model, the C(kappa)-region mRNA could have originated from: (i) translocation of this V gene to the C gene, deletion of the entire mature V gene, and "end-to-end" repair of the remaining xp-DNA to the C gene; (ii) translocation to the C gene only of the xp-DNA portion of the V gene. Alternatively, we may assume that the xp-DNA is not covalently linked to the mature V gene at all times, as might be the case for the DNA of hypervariable regions presumed to be in episomes. This raises the intriguing speculation that the xp-DNA represents a third distinct gene, designated xp-gene. The presumed xp-gene may be involved in the regulation of gene transcription: when linked to the mature V gene it initiates a chain of events leading to whole L-chain mRNA formation; when attached to the C gene it leads to its transcription to provide the C-region mRNA.
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PMID:Independent expression of the gene coding for the constant domain of immunoglobulin light chain: evidence from sequence analyses of the precursor of the constant region polypeptide. 41 16

It was previously shown that digestion of human IgG1/kappa myeloma proteins with pepsin in the presence of 8 M-urea produces fragments which differ from other proteolytic fragments of IgG, including those produced by peptic digestion in aqueous buffers. The two large urea/pepsin fragments each consist of three peptides, and together account for all of the constant region of the light chains and most of the constant region of the heavy chains. Myeloma proteins of subclasses IgG2, IgG3 and IgG4 with kappa light chains were digested with pepsin in 8 M-urea, and the resulting fragments compared with those produced from IgG1/kappa proteins. Gel filtration, starch- and polyacrylamide-gel electrophoresis and sequence analysis have shown that the peptides from each subclass are analogous with those from IgG1. A brief investigation of the products of urea/pepsin digestion of myeloma proteins with lambda light chains has shown that in these proteins light-chain cleavage occurs at residue leucine-182, instead of or as well as at residue 117, where cleavage takes place in kappa chains. Comparison of sequences around sites of urea/pepsin cleavage has shown that pepsin has quite restricted specificity under these conditions.
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PMID:Fragments produced by digestion of human immunoglobulin G subclasses with pepsin in urea. 41 84


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