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)

A family of cytokines [IL-6, IL-11, oncostatin M (OM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1] involved in various inflammatory or tumoral diseases share the same gp130 signal transducer chain. The complex formed with their specific receptors associates with a common transducing gp130 membrane protein (gp130) resulting in the formation of high avidity receptor and activation of tyrosine kinases. With the view of identifying gp130 domains specifically involved in IL-6 signalling, the authors prepared 37 new anti-gp130 mAb and analysed the structure-function relationship of the molecule. By cross-competition ELISA, the mAb were classified in 10 subgroups called A to J. By ELISA and BIAcore analysis, the mAb were found to recognize at least 18 antigenic specificities of the gp130 chain. The mAb reacted against the soluble and the membrane forms of gp130 as well. Their ability to inhibit the proliferation of the human myeloma cell line XG-4 of which the growth is strictly dependent on the presence of either exogenous IL-6, or LIF, or OM, or CNTF was studied. Besides mAb with no evident neutralizing effect (G and H) and mAb which neutralized equally well the activity of all tested cytokines (all mAb of groups A, I and J), some showed a selective effect. Those of group F inhibited also the proliferation induced by the 4 cytokines, but more specifically that dependent on the CNTF. mAb of groups B and E specifically inhibited the growth induced by IL-6, whereas those of group C inhibited that induced by LIF and OM. These results show the presence of different gp130 epitopes specifically involved in the signaling induced by the cytokines of the gp130 family. In ELISA, only mAb of group B and E were found to inhibit the binding of the IL-6-IL-6R complex to gp130, showing that they identified one or two domains of gp130 involved in its interaction with the IL-6-IL-6R complex. Precise identification of this(ese) epitope(s) would be useful to better understand the mechanisms of the IL-6 signalling.
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PMID:Specific inhibition of IL-6 signalling with monoclonal antibodies against the gp130 receptor. 911 31

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 represent a common mechanism of oncogene activation in lymphoid malignancies. In multiple myeloma (MM), the most consistent chromosomal abnormality is the 14q+ marker, which originates in one third of cases through a t(11; 14)(q13; q32) chromosomal translocation; in the remaining cases, the identity of the partner chromosomes has not been well established. We used a Southern blot approach based on the linkage analysis of the joining (J) and the constant (C) mu, alpha, and gamma regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 nonkaryotyped patients with MM (78 cases) or plasma cell leukemia (PCL) (10 cases) and found the presence of "illegitimate" rearranged IGH fragments (no comigration between the J and C regions) in 21 cases. To confirm this analysis, we cloned the illegitimate rearranged fragments from three samples, and the molecular and fluorescent in situ hybridization (FISH) analyses indicated the presence of chromosomal translocations juxtaposing a switch IGH region to sequences from chromosomes 11q13 (one PCL case) or 4p16.3 (two MM cases). Interestingly, the breakpoints on 4p16.3 occurred about 14 kb apart in a genomic region located approximately 50 kb centromeric to the fibroblast growth-factor receptor 3 (FGFR3) gene. Moreover, Southern blot analysis using 4p16.3 genomic probes detected a rearrangement in an additional MM tumor. FISH analysis of the MM-derived KMS-11 cell line, reported to be associated with a t(4; 14)(p16.3; q32), showed that the FGFR3 gene was translocated on 14q32. High levels of FGFR3 mRNA expression were observed in the cloned MM tumors and KMS-11 cell line, but not in the cases that were apparently negative for this lesion. Furthermore, a point mutation at codon 373 in the transmembrane domain of the FGFR3 gene resulting in an amino acid substitution (Tyr --> Cys) was detected in the KMS-11 cell line. These findings indicate that the t(4; 14)(p16.3; q32) represents a novel, recurrent chromosomal translocation in MM, and suggest that the FGFR3 gene may be the target of this abnormality and thus contribute to tumorigenesis in MM.
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PMID:A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. 976 94

Binding of interleukin-6 to its receptor (IL-6R) induces the association of the IL-6R alpha chain (IL-6Ralpha) with a 130-kDa transmembrane glycoprotein, gp130. This event activates tyrosine kinases of the Janus kinase (JAK) family and transduces signals to the cytosol or nucleus. To further characterize the biochemical mechanisms by which IL-6 promotes cell proliferation, we investigated the effects of IL-6 on the growth and transmembrane signaling of several lymphoid cell lines. In the IL-6-dependent cell line B-9, IL-6 induced a rapid, transient, and concentration-dependent tyrosine phosphorylation of several cytosolic proteins as detected by antiphosphotyrosine immunoblots. The molecular weight of major bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis was 44, 65, 70, 80, 137, 148, 184, and 190 kDa, respectively. Similar effects of IL-6 on tyrosine phosphorylation were observed in the human multiple myeloma cell line LP-1. Because JAKs were unlikely to mediate all the biological effects of IL-6, we investigated whether members of the Src family of tyrosine kinases were also activated in B-9 or LP-1 cells. IL-6 induced the activation and tyrosine phosphorylation of p59Fyn, p56/59Hck, and p56Lyn. Coprecipitation experiments with anti-Hck, anti-Lyn, anti-Fyn, and anti-gp130 antibodies revealed a physical association with gp130 of p56/59Hck and p56Lyn, but not p59Fyn, in LP-1 cells. Together, these results show for the first time that several Src kinases may become activated by IL-6 (p59Fyn, p56/59Hck, and p56Lyn) and associate with gp130 (p56/59Hck and p56Lyn).
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PMID:Signal transduction of interleukin-6 involves tyrosine phosphorylation of multiple cytosolic proteins and activation of Src-family kinases Fyn, Hck, and Lyn in multiple myeloma cell lines. 940 96

Interactions between P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) mediate the earliest "rolling" of leukocytes on the lumenal surface of endothelial cells at sites of inflammation. Previously, PSGL-1 has been shown to be the primary mediator of interactions between neutrophils and P-selectin, but studies on the ability of PSGL-1 to mediate interactions between P-selectin and other subsets of leukocytes have yielded variable and conflicting results. A novel IgG monoclonal antibody (MoAb) to human PSGL-1 was generated, and the specificity of this MoAb was confirmed by both flow cytometric analysis and Western blotting of cells transfected with human PSGL-1. This newly developed MoAb, KPL1, inhibited interactions between P-selectin expressing COS cells and either HL60 cells, neutrophils, or lymphocytes. Furthermore, KPL1 completely inhibited interactions between P-selectin and either purified CD4 T cells or neutrophils in a flow assay under physiological conditions, but had no effect on interactions of T cells or neutrophils with E-selectin. In addition, KPL1 blocked interactions between lymphoid cells transfected with L-selectin and COS cells expressing PSGL-1. The KPL1 epitope was mapped to a site within a consensus tyrosine sulfation motif of PSGL-1, previously shown to be essential for interaction with P-selectin and now shown to be essential for interaction with L-selectin, and to be distinct from the epitope identified by the PL1 function blocking anti-PSGL-1 MoAb. Two-color flow cytometry of normal leukocytes showed that while natural killer (NK) cells (CD16(+)), monocytes, CD4 and CD8 T cells, and alpha/beta and gamma/delta T cells were uniformly positive for PSGL-1, B cells expressed low levels of the KPL1 epitope. This low level of KPL1 staining was also observed immunohistologically in germinal centers, which had no detectable KPL1 staining, whereas T-cell areas (interfollicular region) were positive for KPL1. Interestingly, plasma cells in situ and interleukin-6-dependent myeloma cell lines were KPL1(+). Thus, PSGL-1 is expressed on essentially all blood neutrophils, NK cells, B cells, T cells, and monocytes. Variation in tyrosine sulfation during B-cell differentiation may affect the ability of B cells to interact with P- and L-selectin.
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PMID:A novel P-selectin glycoprotein ligand-1 monoclonal antibody recognizes an epitope within the tyrosine sulfate motif of human PSGL-1 and blocks recognition of both P- and L-selectin. 941 80

Of 5 multiple myeloma patients with hyperammonemia, autopsy was performed in 4 patients, while amino acid metabolism was examined in 3 patients. As a result they were classified into the following 3 types; A, liver dysfunction and severe liver infiltration of myeloma cells. B, severe liver infiltration without liver dysfunction. C, Neither liver dysfunction nor severe liver infiltration. In one type A patient, isoleucine decreased. In two patients without liver dysfunction (one type C patient and another patient in whom autopsy was not performed) valine, leucine and isoleucine decreased, and tyrosine decreased slightly. The Fischer ratio decreased in these 2 patients, while it decreased slightly in a type A patient. Clinically, in 4 patients hyperammonemia was observed during periods of poor general condition and when refractory to chemotherapy. In an aggressive type case, consciousness disturbance was developed rapidly and multiple myeloma was diagnosed. In all patients, consciousness disturbance was noted. Hyperammonemia might have been caused by hepatic failure or systemic-portal shunt in patients with liver infiltration. In those without liver infiltration, it was suggested that hyperammonemia was caused by myeloma related humoral factors that influence amino acid metabolism.
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PMID:[Clinicopathological study of multiple myeloma associated with hyperammonemia]. 949 50

Evidence suggests that cellular adhesion is critical for eosinophil effector functions. Here, we tested the hypothesis that an adhesion molecule, specifically beta2 integrin, participates in intracellular signaling events of eosinophils. Eosinophils stimulated with interleukin (IL)-5 and adherent to protein-coated tissue culture plates via beta2 integrin (CD18) showed tyrosine phosphorylation of a number of proteins. Among these proteins, tyrosine phosphorylation of the 105 kD and 115 kD proteins and the product of the c-cbl protooncogene, Cbl, was specifically inhibited using soluble anti-CD18 monoclonal antibody (mAb) to block eosinophil cell adhesion. Furthermore, phosphoinositide turnover of IL-5-stimulated adherent eosinophils was also inhibited by anti-CD18 mAb, suggesting that cellular adhesion plays important roles in eosinophil signal transduction. alphaM beta2 (Mac-1, CD11b/18) was one of the beta2 integrins involved in eosinophil adhesion to protein-coated plates. We found that direct ligation of eosinophil alphaM beta2 with anti-CD11b mAb coupled to polystyrene microbeads induced tyrosine phosphorylation of a 115 kD protein and Cbl. Furthermore, anti-CD11b mAb microbeads induced increases in both phosphoinositide hydrolysis and the eosinophil degranulation response. Control antibodies, such as mouse myeloma IgG1 and anti-HLA class I antigen mAb, did not induce these cellular responses. These results suggest that engagement of beta2 integrin either by cell adhesion or by anti-CD11b mAb triggers activation of an intracellular signaling cascade, including protein tyrosine phosphorylation and phosphoinositide turnover, and subsequent cellular degranulation in human eosinophils. Tyrosine phosphorylation of a 115 kD protein and Cbl may play important roles in adhesion-dependent cellular functions of eosinophils.
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PMID:Ligation of the beta2 integrin triggers activation and degranulation of human eosinophils. 956 38

To analyze the cellular antigens of human B-cell lineage, a monoclonal antibody, NU-B1, was raised using the acute lymphoblastic leukemia (ALL) cell line NALM-16 as the immunogen. NU-B1 reacted with 7.7+/-3.9% of the healthy adult peripheral blood mononuclear cells but not with neutrophils, monocytes, red blood cells or thymocytes. In order to distinguish the reaction specificity of NU-B1, two-color immunofluorescence staining using tonsillar cells was performed, and it was demonstrated that NU-B1-positive cells coexpressed CD20, which is a representative B-cell antigen. The expression of NU-B1 was highly restricted to cells of B-cell lineage when a panel of hematopoietic cell lines was examined. In a pathoimmunohistological study using human lymph node tissue, NU-B1-positive cells were localized in the mantle and marginal zones. In a clinical study, NU-B1 reacted specifically with leukemias/lymphomas of B-cell lineage: all 43 cases of ALL including common ALL and biphenotypic leukemia, all 4 cases of B-cell ALL, 6/7 B-cell type malignant lymphomas and 2/4 B-cell chronic lymphocytic leukemias. NU-B1 did not react with multiple myeloma, T-cell or myeloid leukemias/lymphomas. Immunoprecipitation of NU-B1 revealed two clear bands at 50 kDa and 42 kDa under either reducing or nonreducing conditions. Although anti-IgM treatment induced dramatic down modulation of CD79b, the NU-B1 antigen was also down modulated, but only slightly. However, crosslinking of NU-B1 did not induce tyrosine phosphorylation of intracellular proteins or the mobilization of calcium in NALM-16. The present results revealed that the antigenic determinant recognized by NU-B1 is not surface immunoglobulin chains, HLA-DR, a receptor for C3, Fc for immunoglobulin chains or any known CD molecule. We conclude that monoclonal antibody NU-B1 recognizes a novel human B-cell restricted antigen distinct from known CD molecules, and that it is a useful antibody in the immunophenotyping and classification of leukemias/lymphomas.
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PMID:Monoclonal antibody NU-B1 reacts with novel antigen on human B cells in mantle and marginal zones distinct from known CD molecules. 986 31

We have recently reported that besides the most abundant form epsilonS1, there exists another human secretory epsilon H chain isoform, epsilonS2, resulting from alternative splicing in the epsilonCH4 exon. Using a specific antibody targeted to the epsilonS2-specific C-terminal tailpiece, we now show that this second secretory IgE isoform (IgE-S2) is constitutively co-expressed with the classical secretory IgE-S1 by human myeloma cells. The epsilonS2 variant was also detected in tonsils and in the serum of three non-atopic donors, but was absent in the vast majority of sera of both atopic and non-atopic individuals tested, indicating rare serum expression. IgE-S2 is capable of binding to cells expressing Fc epsilonRI, the high-affinity receptor for IgE. Analysis of intracellular tyrosine phosphorylation signal, degranulation, and rate of receptor internalization suggest a quantitatively lower response by IgE-S2 compared to IgE-S1. The modest differences observed do not appear to overall affect the degranulation competency of IgE-S2, but suggest that the unique structure of the epsilonS2 tailpiece can exert an effect on the interaction with the alpha chain of Fc epsilonRI.
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PMID:Functional Fc epsilonRI engagement by a second secretory IgE isoform detected in humans. 1009 98

Bruton's tyrosine kinase (Btk) plays a critical role in B cell Ag receptor (BCR) signaling, as indicated by the X-linked immunodeficiency and X-linked agammaglobulinemia phenotypes of mice and men that express mutant forms of the kinase. Although Btk activity can be regulated by Src-family and Syk tyrosine kinases, and perhaps by phosphatidylinositol 3,4,5-trisphosphate, BCR-coupled signaling pathways leading to Btk activation are poorly understood. In view of previous findings that CD19 is involved in BCR-mediated phosphatidylinositol 3-kinase (PI3-K) activation, we assessed its role in Btk activation. Using a CD19 reconstituted myeloma model and CD19 gene-ablated animals we found that BCR-mediated Btk activation and phosphorylation are dependent on the expression of CD19, while BCR-mediated activation of Lyn and Syk is not. Wortmannin preincubation inhibited the BCR-mediated activation and phosphorylation of Btk. Btk activation was not rescued in the myeloma by expression of a CD19 mutant in which tyrosine residues previously shown to mediate CD19 interaction with PI3-K, Y484 and Y515, were changed to phenylalanine. Taken together, the data presented indicate that BCR aggregation-driven CD19 phosphorylation functions to promote Btk activation via recruitment and activation of PI3-K. Resultant phosphatidylinositol 3,4,5-trisphosphate probably functions to localize Btk for subsequent phosphorylation and activation by Src and Syk family kinases.
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PMID:Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. 1020 80

All-trans retinoic acid (ATRA) has previously been shown to inhibit the growth of OPM-2 human myeloma cells. The growth inhibition was postulated to result from a transcriptional downregulation of interleukin-6 receptor alpha (IL-6Ralpha) with IL-6Rbeta (gp130) unaffected. To formally test this hypothesis, an expression vector designed for constitutive IL-6Ralpha expression was constructed and used for transfection of OPM-2 cells. Six stable transfectants were cloned. The expression of IL-6Ralpha was shown by immunofluorescence with anti-IL-6Ralpha antibody and 125I-IL-6 binding. In five of six transfectant clones, cellular IL-6Ralpha was 1.5- to 6-fold higher than the parental cells, with the ligand binding affinity unchanged. While ATRA reduced IL-6Ralpha expression in the parental OPM-2 cells, it enhanced its expression in these five transfectants. The clonogenic growth of these transfectants, however, remained strongly inhibited by ATRA. Further analysis, comparing the parental OPM-2 cells and a representative transfectant, clone C5, showed that IL-6 caused rapid tyrosine phosphorylation of gp130 in both OPM-2 and C5 clones. Pretreatment with ATRA greatly reduced IL-6-induced gp130 phosphorylation in OPM-2 cells, reflecting a reduction in cellular IL-6Ralpha. In contrast, IL-6-induced gp130 phosphorylation was not reduced by ATRA pretreatment in C5 cells, indicating that the expressed IL-6Ralpha was functional. Similar to OPM-2 cells, C5 cells were sensitive to growth inhibition by dexamethasone, which was entirely reversed by exogenous IL-6, suggesting that the IL-6 postreceptor signal transduction remained intact. ATRA was further shown to upregulate p21(WAF1) expression and cause dephosphorylation of the retinoblastoma protein (pRB) in both OPM-2 and C5 cells. Exogenous IL-6 also failed to reverse these effects of ATRA. Thus, the growth inhibitory activity of ATRA is not mediated through cellular IL-6Ralpha downregulation and is likely to result from a direct upregulation of p21(WAF1) and consequent dephosphorylation of pRB.
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PMID:Growth inhibition of a human myeloma cell line by all-trans retinoic acid is not mediated through downregulation of interleukin-6 receptors but through upregulation of p21(WAF1). 1038 20


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