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 human monoclonal antibody which reacts preferentially with HLA-DR4 and -DRw10 B-cell targets has been produced. A human B-cell line, secreting antibody which reacted preferentially with DR4 and DR1 targets, was derived from a highly sensitized kidney recipient who had rejected two grafts. This line was fused with the mouse myeloma P3X63Ag8.653 and a selected hybridoma cloned. The clones secrete IgM(lambda), which reacts strongly with HLA-DR4 and -DRw10 and more weakly with -DRw14 and a proportion of -DR1 B cells in cytotoxicity assays. Using B-cell lines as targets in cytotoxicity and enzyme-linked immunosorbent assays, the antibody gives a broader pattern of reaction, reacting with HLA-DR1, -DR4, -DR9, -DRw10, -DRw14, and some -DR2 targets. The antibody (NI) is currently in use as a reagent for tissue typing.
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PMID:Production of a cytotoxic human monoclonal antibody with specificity for HLA-DR4 and -DRw10 by cells derived from a highly sensitized kidney recipient. 197 Dec 67

Anemia is a prominent feature of multiple myeloma (MM) and is commonly associated with clinical progression of MM. In addition to being affected by a number of pathogenetic events, including imbalance of the cytokine network, inappropriate erythropoietin (EPO) levels, blood loss, and hemolysis, the erythroid matrix is chronically deteriorated by the malignant plasma cell clone that activates a cytotoxic mechanism directed at the erythroid progenitors. In particular, malignant plasma cells express very high levels of apoptogenic receptors, including both Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand, which trigger apoptosis of immature erythroblasts by stimulating specific death receptors, namely Fas and the complex DR4/DR5. Erythroid cells also weakly express the transcription factor GATA-1, which drives erythroblast maturation by inhibiting apoptosis through antiapoptotic molecules such as EPO and Bcl-xL. This newly discovered pathogenetic mechanism of anemia in MM is based on persistent erythroblast cytotoxicity within the bone marrow that leads to progressive destruction of the erythroid matrix.
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PMID:Recent advances in understanding the pathogenesis of anemia in multiple myeloma. 1295 5

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DR5), and 2 potentially antiapoptotic receptors lacking death domains (DcR1 and DcR2). Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70-100%. Treatment with 5-aza-2'-deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated.
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PMID:Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. 1499 91

Bone remodelling is severely affected in myeloma bone disease as a consequence of skeletal metastatization of malignant plasma cells. We investigated whether defective bone replacement is dependent on increased osteoblast apoptosis and/or on deregulated events within the bone microenvironment. Circulating tumour necrosis factor (TNF)-alpha, interferon-gamma, interleukin (IL)-1beta, and IL-6 levels were higher in myeloma patients with overt bone disease, whose osteoblasts constitutively overexpressed Fas, DR4/DR5 complex as receptors to TNF-related apoptosis inducing ligand, intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1). They were functionally exhausted and promptly underwent apoptosis in vitro, in contrast to the minor tendency to death detected in control osteoblasts from patients without bone involvement and normal donors. Osteoblasts dramatically enhanced their apoptosis in co-cultures with MCC-2 myeloma cells and upregulated both ICAM-1 and MCP-1 in a manner similar to control osteoblasts. Pretreating MCC-2 cells with soluble ICAM-1 led to a striking inhibition of their adhesion to osteoblasts, suggesting that the ICAM-1/lymphocyte function-associated antigen-1 system plays a role in the reciprocal membrane contact to trigger apoptogenic signals. Our data suggest that, in the myeloma bone microenvironment, both high cytokine levels and physical interaction of malignant plasma cells with osteoblasts drive the accelerated apoptosis in these cells leading to defective new bone formation.
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PMID:Impaired osteoblastogenesis in myeloma bone disease: role of upregulated apoptosis by cytokines and malignant plasma cells. 1528 39

The development of multiple myeloma (MM) bone disease is mediated by increased number and activity of osteoclasts (OCs). Using an in vitro osteoclastogenesis model consisting of unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) from patients with MM, we showed that T cells support the formation of OCs with longer survival. Different from T-cell-depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) were necessary for the formation of OCs; however, they did not exhibit longer survival. We found up-regulated production of RANKL, osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) by fresh MM T cells. Despite high OPG levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex demonstrated by immunoprecipitation experiments and the addition of anti-TRAIL antibody which decreases OC formation. OCs overexpressed TRAIL decoy receptor DcR2 in the presence of MM T cells and death receptor DR4 in T-cell-depleted cultures. In addition, increased Bcl-2/Bax (B-cell lymphoma-2/Bcl2-associated protein X) ratio, following Bcl-2 up-regulation, was detected in OCs generated in the presence of T cells. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction and unbalanced OC expression of TRAIL death and decoy receptors.
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PMID:T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction. 1530 61

Multiple myeloma is a neoplasmatic disease of the hematopoietic system which constitutes about 10% of all hematological proliferations. Anemia is a common symptom of myeloma, especially in patients with advanced disease, and its severity correlates with the clinical stage of myeloma. There are several factors involved in the pathogenesis of anemia in multiple myeloma: infiltration of the bone marrow with monoclonal plasma cells, inadequate secretion of erythropoietin, shortened erythrocyte survival time, dysregulated iron metabolism, impaired marrow function due to proinflammatory cytokine secretion, and interaction between erythroblasts and malignant plasma cells. Recent findings indicate an important function of apoptosis in regulating physiological erythropoiesis. In physiological conditions some erythroblasts undergo apoptosis, which is induced by proteins belonging to the TNF family, i.e. Fas(CD95), FasL(CD95L),and TRAIL (TNF-related apoptosis inducing-ligand) with its receptors--DR4 (Death Receptor 4), and DR5 (Death Receptor 5). Expression of Fas, DR4, and DR5 is detected on the cell membrane of erythroblasts in all stages, whereas FasL and TRAIL are present only in more mature erythroblasts. Interaction of mature erythroblast FasL+/TRAIL+ with immature erythroblast FasL-/TRAIL--results in apoptosis of the immature cell, which contributes to the down-regulation of physiological erythropoiesis. The expression of proteins involved in erythropoiesis regulation is controlled by erythropoietin (EPO), which decreases erythroblast susceptibility to FasL and TRAIL stimulation and prevents apoptosis. On the other hand interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) increase Fas expression on erythroid cells and enhance their apoptosis. Malignant plasma cells show increased expression of FasL and TRAIL and decreased expression of Fas, which make them more resistant to apoptotic signals. FasL+/TRAIL+ plasmocytes are involved in anemia pathogenesis in multiple myeloma patients by inducing apoptosis of erythroid cells. Monoclonal plasmocytes also secrete numerous cytokines involved in plasma cell growth, bone marrow neovascularisation and anemia.
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PMID:[Involvement of apoptosis and proinflammatory cytokines in the pathogenesis of anemia in multiple myeloma]. 1553 94

In this study, we have evaluated the cytotoxic effect of combining two HDAC inhibitors, SAHA and TSA, with TRAIL in human multiple myeloma cell lines. Low doses of SAHA or TSA enhanced the cytotoxic and apoptotic effects of TRAIL and upregulated the surface expression of TRAIL death receptors (DR4 and/or DR5). SAHA and TSA induced G1 phase cell cycle growth arrest by upregulating p21(WAF1) and p27(Kip1) expression and by inhibiting E2F transcriptional activity. The enhanced TRAIL effect after pretreatment with HDAC inhibitors was consistent with the upregulation of the proapoptotic Bcl-2 family members (Bim, Bak, Bax, Noxa, and PUMA), the downregulation of the anti-apoptotic members of the Bcl-2 family (Bcl-2 and Bcl-X(L)), and IAPs. SAHA and TSA dissipated the mitochondrial membrane potential and enhanced the release of Omi/HtrA2 and AIF from the mitochondria to the cytosol. The cytotoxic effect of both SAHA and TSA was caspase- and calpain-independent. Inhibition of NF(kappa)B activation by the proteasome inhibitor, MG132, enhanced the apoptotic effect of TSA. Our study demonstrated the enhancing effects of HDAC inhibitors on apoptosis when combined with TRAIL and, for the first time, emphasized the role of AIF in mediating the cytotoxic effects of HDAC inhibitors.
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PMID:Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. 1602 44

Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain-containing protein, and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid, were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-X(L) overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation, and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L) independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft-mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis.
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PMID:Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. 1700 75

The growth and survival of myeloma cells is critically regulated by cells of the bone marrow microenvironment, including osteoblasts. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of myeloma cell apoptosis, however, this antimyeloma activity is inhibited by osteoprotegerin (OPG) released from osteoblasts. Therefore, we hypothesized that specific agonists of TRAIL death receptors would not be inhibited by OPG released from osteoblasts and thus may represent a novel therapeutic approach in multiple myeloma. In the present study, TRAIL-induced apoptosis was demonstrated to be mediated through both DR4 and DR5. Specific agonist antibodies to DR4 or DR5 dose-dependently induced myeloma cell apoptosis, which was not prevented by OPG or by medium conditioned by osteoblasts. Co-culture of myeloma cells with osteoblasts protected against TRAIL-induced apoptosis of myeloma cells, and this protective effect was due to OPG. In contrast, the co-culture of myeloma cells with osteoblasts had no protective effect on apoptosis induced by specific agonists of DR4 or DR5. TRAIL has been proposed as a potential antitumour therapy, but within the bone marrow microenvironment OPG may interfere with the action of TRAIL. Specific agonists of TRAIL death receptors would not be subject to this inhibition and thus may provide an alternative specific antimyeloma therapy.
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PMID:Agonists of TRAIL death receptors induce myeloma cell apoptosis that is not prevented by cells of the bone marrow microenvironment. 1731 27

The improved recombinant form of the death ligand Apo2L/TRAIL (Apo2L/TRAIL.0) is not cytotoxic for normal human cells and is a good candidate for the therapy of multiple myeloma (MM), a B-cell neoplasia that remains incurable. We have analyzed the molecular determinants of myeloma sensitivity to Apo2L/TRAIL.0 in a number of MM cell lines, the mechanisms of resistance and a possible way of overcoming it. Expression of one death receptor for Apo2L/TRAIL (DR4 or DR5) is sufficient to transduce death signals, though DR5 was more efficient when both receptors were present. Membrane expression of decoy receptors (DcR1, DcR2) and intracellular levels of c-FLIP(L), XIAP and Mcl-1 were not predictive of resistance to Apo2L/TRAIL. Inhibition of Mcl-1 degradation did not prevent Apo2L/TRAIL-induced apoptosis. In IM-9 cells, resistance was associated to a reduced caspase-8 expression. U266 cells, though expressing significant levels of DR4 and caspase-8, were nevertheless resistant to Apo2L/TRAIL. This resistance could be overcome by co-treatment with valproic acid (VPA), a histone deacetylase inhibitor. VPA caused the redistribution of DR4 to plasma membrane lipid rafts and restored DR4 signaling. Overexpression of Mcl-1 in U266 cells did not prevent Apo2L/TRAIL cytotoxicity in VPA-sensitized cells. These results, taken together, support the possible use of Apo2L/TRAIL.0 in the treatment of MM.
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PMID:Membrane expression of DR4, DR5 and caspase-8 levels, but not Mcl-1, determine sensitivity of human myeloma cells to Apo2L/TRAIL. 1746 28


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