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

A considerable amount is known about Ig biosynthesis by mature plasma cells, which form large amounts of Ig for secretion from the cell. A brief summary is given of the formation of light (L) and heavy (H) chains by polyribosomes aligned on the endoplasmic reticulum and the rapid assembly of the chains into 7S molecules (H2L2) by disulphide bonding. There is a time-ordered secretion from the cell of 7S Ig molecules; the polymeric forms of Ig, ie, IgM and IgA, are formed from monomers by disulphide bond interchange and J chain incorporation at the time of secretion. Myeloma cells from mouse and man have proved very useful in this type of study but such malignant cells show many defects in regulatory mechanisms; therefore, no conclusions can be drawn about normal control mechanisms without analysis of lymphoid tissues from normal or immunized animals. The pattern of Ig synthesis by the mature cell contrasts with that by small B lymphocytes which form 1/50 to 1/100 the amount of Ig produced by mature cells. Most of the small lymphocyte Ig is associated with the cell surface, and in IgM-producing cells the surface receptors are 7S monomer subunits of IgM. Such receptors turn over slowly (24-48 hours); they may be gradually shed from the cell surface but the small lymphocyte does not actively secrete Ig. Antigen- and cell-cell interactions stimulate small B lymphocytes to divide and mature into Ig-secreting cells. Little is known about the associated intracellular events, but preliminary data on lipopolysaccaride-stimulated mouse spleen cells indicate that transcription of m-RNA for H-chain mirrors the kinetics of DNA synthesis. A translational block then occurs during cell maturation and there is a lag of at least 24 hours before Ig production rises sharply and reaches peak levels.
 ...
PMID:Immunoglobulin formation in B lymphoid cells. 80 75

Patients with IgG multiple myeloma underwent serial studies of tumor cell kinetics including (1) estimation of the total body myeloma cell number (TBMC), (2) measurement of the myeloma cell tritiated thymidine labeling index (LI), and (3) calculation of the total number of myeloma cells undergoing DNA synthesis. Intermittent courses of chemotherapy with cycle-non-specific agents such as melphalan resulted in a marked increase in the LI of myeloma cells in patients who had a 75% reduction in TBMC. The long "plateau" phase of partial remission of myeloma in these patients was associated with a continued high LI: this suggests that the plateau resulted from a balance between the cytoreductive effects of chemotherapy and expansion of the growth fraction (GF) of the tumor. Preliminary attempts to capitalize therapeutically on this expansion of the GF in several patients included administration of the cycle-active agents vincristine and cytosine arabinoside. Vincristine appeared to induce a further reduction in tumor in several patients, although cytosine arabinoside appeared to be ineffective despite clear evidence of its inhibition of DNA synthesis in myeloma cells in vivo. Further clinical studies of the effects of cycle-active drugs on myeloma appear to be warranted; however, successful exploitation of the dynamic change in myeloma cell kinetics with chemotherapy will require the use of cycle-active agents with marked selective toxicity for myeloma cells.
 ...
PMID:Expansion of the growth fraction in multiple myeloma with alkylating agents. 80 4

32P-labeled light chain messenger RNA was prepared from mouse MOPC 21 myeloma cells. The messenger RNA was hybridized to purified repetitive nuclear DNA and both the hybridized (repetitive 32P-RNA) and nonhybridized (nonrepetitive 32P-RNA) fractions were isolated. Only the nonhybridized RNA gave a T1 ribonuclease fingerprint showing oligonucleotides derived from the variable and constant regions of the light chain messenger RNA. In addition, this fingerprint showed oligonucleotides derived from the untranslated regions of the light chain messenger RNA. The nonrepetitive 32P-RNA was shown to rehybridize only with the unique fraction of total nuclear DNA. The rapidly hybridizing part of the unfractionated 32P-RNA preparation, therefore, is not a component of the light chain messenger RNA itself. Complementary DNA was prepared with reverse transcriptase using unlabeled light chain messenger RNA as template, and the transcripts were fractionated into various size classes. Complementary DNA molecules greater than 900 bases in length hybridized with both the initial messenger RNA and with the nonrepetitive 32P-RNA but failed to hybridize with excess purified repetitive 32P-RNA. The rapidly hybridizing component of the messenger RNA fraction, therefore, does not appear to be transcribed by reverse transcriptase. It is concluded that, under the experimental conditions used, the light chain messenger RNA hybridizes exclusively with unique DNA.
 ...
PMID:Demonstration that a mouse immunoglobulin light chain messenger RNA hybridizes exclusively with unique DNA. 80 42

SP 104 is an IgA-kappa myeloma protein produced by a lymphoid tumour of CA F1 mice. It arose originally in mice injected intraperitoneally with cell-free extract of spleen from a dog with systemic lupus erythematosus. The monoclonal nature of the IgA was shown by characteristic appearance on immunoelectrophoresis, restriction to a single light chain type and ability to induce anti-idiotypic antiserum. This protein has antibody activity against native (double-stranded) DNA and its specificity is similar to the antibodies against DNA found in the sera of humans with SLE and NZB/NZW F1 mice. Its idiotype does not cross-react with idiotypes of other mouse myeloma proteins known to bind DNA.
 ...
PMID:An unusual mouse myeloma protein binding native DNA. 81 22

RNA fractions rich in immunoglobulin light (L)-chain mRNA were isolated from mouse myeloma MOPC 41 by procedures previously described, and chemically labeled with 125I. These RNA fractions were hybridized with MOPC 41 DNA under conditions of DNA excess. Hybridization conditions were chosen under which the entire sequence of the L-chain mRNA probe, thus including the variable region, remains available for hybridization throughout the reaction. The hybridization (C0t) curve showed double transition kinetics, with one component corresponding to about 250 gene copies and the other to about two to four copies. In contrast, when MOPC 41 L-chain mRNA was further purified as a single band by gel elecptrophoresis in 99% formamide, the hybridization curve showed only a single transition, corresponding to about two to four genes, with the disappearance of the "reiterated" component. That component resulted therefore from contaminating RNA species. The data indicate that no reiteration can be detected by RNase or by hydroxylapatite for the genes corresponding to the entire sequence of MOPC 41 L-chain mRNA, including the untranslated segments, within the limits of detectability of short reiterated segments. It thus appears that there is only one or very few genes corresponding to the 41 L-chain variable region "subgroup" in MOPC 41 DNA. The possibility that the variable genes of plasmocytes might result frm a combination of several nonreiterated germline genes is discussed.
 ...
PMID:No detectable reiteration of genes coding for mouse MOPC 41 immunoglobulin light-chain mRNA. 81 7

Messenger RNA sequences for immunoglobulin kappa light chain were synthesized in vitro in isolated mouse myeloma nuclei using bound endogenous RNA polymerase (RNA nucleotidyltransferase; nucleoside triphosphate:RNA nucleotidyltransferase; EC 2.7.7.6) and from isolated myeloma chromatin using exogenous Escherichia coli RNA polymerase. The in vitro RNA was transcribed using 5-mercuriuridine triphosphate and separated from in vivo RNA by chromatography on an agarose sulfhydryl affinity column. Template restriction is retained in vitro since synthesis of kappa chain messenger RNA, As determined by hybridization with complementary DNA, was much more efficient in nuclei and chromatin isolated from myeloma 66.2 tissue culture cells, a kappa-chain-producing cell line, than from MOPC 315 tissue culture cells, a lambda-chain-producing cell line. Transcription of kappa chain messenger RNA was 25 times more efficient in myeloma 66.2 nuclei than in myeloma 66.2 chromatin.
 ...
PMID:Transcription in vitro of immunoglobulin kappa light chain genes in isolated mouse myeloma nuclei and chromatin. 81 8

Immunoglobulin kappa-chain mRNA was hybridized with DNA in order to assess the kappa-gene frequency. Kappa-mRNA was purified from membrane-bound ribosomes of mouse myeloma MOPC-41 by poly (U) chromatography and isolation of a 13S RNA by successive sucrose density gradient centrifugations. The RNA coded for kappa-chain precursor molecules in cell-free protein synthesis and essentially no other proteins. MOPC-41 kappa-mRNA hybridized with MOPC-41, MPC-11, and Krebs DNA with the same kinetics: the majority of the hybrids was formed with rare or unique DNA sequences (Cot/2 450 to 900), a small portion with highly repetitive sequences (Cot/2 5--6). The slow hybrids were well matched and the rapid hybrids were mismatched by about 4%, regardless of the DNA used. It was further investigated whether the rapid hybrids contained translatable kappa-mRNA or were due to impurities in the RNA preparations. Kappa-mRNA and globin-mRNA (as an internal standard for a unique transcript) were hybridized with DNA to Cot 20 or 48, the hybridized and unhybridized RNA were isolated by hydroxyopatite-urea chromatography and, after removal of the DNA, translated in a cell-free system. The cell-free products were analyzed by SDS-polyacrylamide gel electrophoresis and immunoprecipitation. It was found that approximately equal quantities of translatable kappa- and globin-mRNA were hybridized maximally 1.7%). The results do not support the hypothesis that kappa-mRNA is a transcript of both repetitive and unique DNA sequences.
 ...
PMID:Analysis of immunoglobulin genes: DNA/RNA hybridization with immunoglobulin kappa-chain mRNA and isolation and translation of hybridized RNA. 81 83

We have synthesized and characterized cDNA complementary to purified mRNA derived from the lambda chain producing myeloma tumor, RPC-20. This cDNA is of sufficinet length to encode the constant region and a major portion of the variable region sequence of the lambda gene. In addition, the expected range of cross-hybridization of this lambda probe has been shown to extend to several different members of the closely related lambda subgroup, as well as to a member of the lambda subgroup represented by MOPC-315. Since there are a minimum of seven known members of the common lambda subgroup in addition to MOPC-315, these sequences, in accordance with the germ line hypothesis, must be represented by a minimum of eight variable region genes. Using the RPC-20 cDNA probe and hybridization kinetic analysis, this sequence was found to be represented as approximately two copies per haploid genome in DNA derived from a variety of k-and lambda-producing tumors and normal tissue. Inasmuch as the cross-hybridization range of the probe has been assessed and a minimum size of the lambda subgroup determined, this observation tends to rule out separate germ line genes corresponding to each individual lambda light chain variant. Certain reservations about these conclusions are discussed.
 ...
PMID:Quantitation of constant and variable region genes for mouse immunoglobulin lambda chains. 82 Mar 72

We investigated by molecular hybridization whether T cells contain RNA sequences homologous to RNA which codes for immunoglobulin kappa-chain (k-chain). A radioactive probe of complementary DNA (cDNA) was prepared by transcription of purified k-chain mRNA from mouse myeloma MOPC-41 with reverse transcriptase (RNA-dependent-DNA nucleotidyltransferase) from avian myeloblastosis virus. The cDNA probably corresponded only to the constant region and 3'-terminus of k-chain mRNA. Kappa-chain cDNA was found to hybridize efficiently with RNA from both thymus cells and an established culture of thymoma cells. The thymus and thymoma cells contained 99.8% and 100% theta-positive cells, respectively. Quantitatively the average thymus T cell (thymus derived lymphocyte) contained about one half as much k-chain mRNA as the average spleen B cell ("bursa" dependent lymphocyte), whereas the thymoma cells contained only 1/33 as much. Control hybridizations of k-chain cDNA with myeloma and liver RNA support the conclusion that T cells in the thymus and in the thymoma cell line synthesize k-chain mRNA-like molecules. The thermal stability of hybrids of k-chain cDNA with RNA from spleen, thymus, thymoma, and another k-chain producing myeloma tumor was lower than that with MOPC-41 RNA. This finding may be due to the existence of several slightly different ck genes in the mouse as suggested by various control experiments.
 ...
PMID:Sequences related to immunoglobulin kappa chain messenger RNA in T cells. 82 Oct 55

To gain information on the origin of antibody diversity (somatic mutation or germ line hypothesis) it is necessary to determine the number of V region genes. For this purpose the capacity of a distinct V region probe to hybridize and quantify V genes of the same and different subgroups should be established. Relevant information on this issue was obtained from the extent of cross-hybridization of a distinct L chain cDNA with mRNAs coding for L chains of the same and different subgroups. The results indicated that: (1) V regions of similar amino acid sequence are coded by similar nucleotide sequence (this is not self-evident because of the degeneracy of the genetic code); (2) the nucleic acid probe to one V region may anneal and quantify V genes of members of the same subgroup. Molecular hybridizations of the cDNA probe with nuclear DNA showed that: (1) the number of kappa type C genes is small (about 2 per haploid genome); (2) the number of V genes presumably is also small; (3) there is no amplification of these genes in myeloma cells that produce large amounts of the Ig. These results support the somatic mutation model for the generation of antibody diversity. New information on the structure and controlled expression of Ig genes was obtained from the study of L chain precursors, which are the immediate product of L chain mRNA translation in vitro. In the precursors extra peptide segments (19-22 residues in length) precede the N-terminus of the mature L chain. Amino acid sequence analyses of the precursors provide evidence that: (1) the gene coding for the V region is larger than hitherto known; (2) duplication of a short DNA segment occurred in the structural gene coding for the MOPC-321 precursor; (3) translation of the L chain mRNA may be contingent on the nucleotide sequence coding for the extra piece; (4) cleavage of the extra piece may regulate secretion of mature L chain; (5) the extra piece is remarkably hydrophobic, suggesting that the role of the extra piece is to anchor the precursor in cell membranes, in a manner similar to the function of the "hydrophobic domain" of membrane bound proteins. We propose that most precursor molecules are directed to the endoplasmic reticulum where the extra piece is cleaved to yield mature Ig destined for secretion; a few precursor molecules escape cleavage and are anchored by means of the hydrophobic extra piece in the cell-surface membrane to serve as the antigen-recognizing receptor.
 ...
PMID:Structure and function of immunoglobulin genes and immunoglobulin precursors. 82 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>