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)

CD95 (APO-1/Fas)-mediated apoptosis plays a major role in normal lymphocyte regulation. CD95 mutations cause a benign autoimmune lymphoproliferation syndrome (ALPS) in mice and humans. CD95 is mutated in some de novo T-lineage acute lymphoblastic leukemia of childhood and these mutations might be of biological significance. The resistance toward CD95-mediated apoptosis observed in most B-lineage ALL is not caused by mutations of CD95. CD95 mutations have been associated with Hodgkin's and Non-Hodgkin's lymphoma and have been described in multiple myeloma. The relevance of CD95 mutations for chemoresistance of ALL requires further study.
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PMID:[The role of CD95 (APO-1/Fas) mutations in lymphoproliferative and malignant lymphatic diseases]. 974 45

A poor response to Fas-induced apoptosis is evident in some multiple myeloma (MM) cell lines and primary cells. In this study, we have examined the possibility to increase the sensitivity to Fas-induced apoptosis by pretreatment of MM cells with interferon-gamma (IFN-gamma) or interferon-alpha (IFN-alpha). Both IFN-gamma and IFN-alpha markedly increased the Fas-induced apoptosis in all cell lines tested (U-266-1970, U-266-1984, and U-1958). In the U-266-1970 and U-1958 cell lines, pretreatment with either IFN-gamma or IFN-alpha also inhibited proliferation in a dose-dependent manner. In contrast, IFN-gamma activation of the Fas death pathway in the U-266-1984 cells was not accompanied by growth inhibition. Incubation with the IFNs increased the Fas antigen expression in one of three cell lines but did not alter the expression of Bcl-2 or Bax. The IFNs are important regulators of growth and survival in MM cells. Our results suggest that activation of Fas-mediated apoptosis is a novel mechanism by which the IFNs exert inhibitory effects on MM cells.
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PMID:Fas/APO-1 (CD95)-mediated apoptosis is activated by interferon-gamma and interferon- in interleukin-6 (IL-6)-dependent and IL-6-independent multiple myeloma cell lines. 976 78

Fas (APO-1/CD95) is a cell-surface receptor involved in cell death signaling. Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma. We have examined the entire coding region and all splice sites of the Fas gene in 150 cases of non-Hodgkin's lymphoma. Overall, mutations were identified in 16 of the tumors (11%). Missense mutations within the death domain of the receptor were associated with retention of the wild-type allele, indicating a dominant-negative mechanism, whereas missense mutations outside the death domain were associated with allelic loss. Fas mutations were identified in 3 (60%) MALT-type lymphomas, 9 (21%) diffuse large B-cell lymphomas, 2 (6%) follicle center cell lymphomas, 1 (50%) anaplastic large cell lymphoma, and 1 unusual case of B-cell chronic lymphocytic leukemia with a marked tropism for skin. Among the 16 patients with somatic Fas mutations, 15 showed extranodal disease at presentation, and 6 relapsed in extranodal areas. Ten of 13 evaluable patients showed features suggestive of autoreactive disease. Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity.
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PMID:Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity. 978 34

IL-6 is a growth factor which interferes in the apoptosis of malignant plasma cells. Here we explore its role in the spontaneous and Fas/FasL-regulated apoptosis of seven myeloma cell clones (MCC). MCC-2 and -7 were constitutively defective in Fas antigen in the presence of large membrane exposure of FasL, and showed a high rate of cell proliferation irrespective of the presence of IL-6. Cytofluorimetric analysis following propidium iodide (PI) staining revealed a minimal extent of spontaneous apoptosis, as in other IL-6-insensitive, though Fas-positive MCC, namely MCC-3 and -5. By contrast, a regular amplitude of apoptosis occurred in the remaining IL-6-dependent clones. Their propensity to cell death, as well as their FasL membrane expression, were promptly down-modulated by the cytokine, whereas no substantial effect was detected in IL-6-independent MCC. Furthermore, we investigated the quantitative secretion of FasL. Both [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) cytotoxicity assay and PI staining of WC8 lymphoblasts from a Fas-transfected mouse lymphoma, incubated with supernatants from MCC, showed a variable cytocidal property, thus confirming the cellular release of FasL. However, a significant elevation of FasL secretion occurred in both Fas- MCC, whereas molecular cloning and sequencing of Fas revealed the presence of a splicing variant, namely Fas Exo4,6Del, in the cDNA from both MCC-3 and -5, which were previously demonstrated to be unresponsive to Fas stimulation. Taken together, these data provide evidence that concurrence of IL-6 insensitivity and deregulation of apoptosis in myeloma cells reflects a high malignancy grade. It is suggested that the secretion of Fas splicing variants in Fas+ plasma cells, as well as the over-production of FasL in Fas- myelomas, are differential mechanisms by which myeloma cells escape host immune surveillance.
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PMID:Fas/Fas ligand (FasL)-deregulated apoptosis and IL-6 insensitivity in highly malignant myeloma cells. 982 74

Although there have been reports regarding the clinical effectiveness of IFN alpha in the treatment of myeloma patients during this decade, its biological effects on human myeloma cells have still not been clarified. Recently, apoptosis has been considered as one of the most important mechanisms in the programmed cell death of malignant tumour cells induced by chemotherapeutic agents or cytotoxic immunological defence in malignancy-carrying hosts. Among the several pathways which function to induce apoptosis, Fas and the Fas ligand system have been thought to play an important role in inducing tumour-cell apoptosis, particularly in immunological prevention. In this study we investigated myeloma cell apoptosis induced by IFN alpha using five human myeloma cell lines which were established without any additional supplementation of IL-6. In addition, the mRNA expression levels of apoptosis-related genes employing the reverse transcriptase-polymerase chain reaction (RT-PCR) were also analysed with the KMS-12-PE cell line, which was the most sensitive of the five cell lines in terms of apoptosis induced by IFN alpha. Based on the results, it was determined that IFN alpha induced myeloma cell apoptosis in a dose-dependent manner, but the sensitivity to IFN alpha in the cell lines examined varied and one cell line revealed growth stimulation by IFN alpha. In addition, the apoptosis induced by IFN alpha did not seem to be mediated by the Fas/Fas ligand pathway. Finally, the IL-6, IL-6R, IRF1 and IRF2 genes were up-regulated in KMS-12-PE cells cultured with IFN alpha. Therefore these genes may play an important role during apoptosis induced by IFN alpha.
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PMID:Human myeloma cell apoptosis induced by interferon-alpha. 982 28

CD95(Fas/APO-1)-ligand (CD95L) mediates apoptosis by trimerization of the CD95 receptor on the surface of sensitive cells. In vitro studies have shown CD95L expression mainly by activated T cells and suggested a role for CD95L in the regulation of immune responses. Little is known, however, about the cellular distribution of CD95L in situ in the normal human immune system. We investigated CD95L expression in tissue sections of the thymus, lymph node, spleen, tonsil, and gastrointestinal tract using in situ hybridization and two monoclonal antibodies. In all these organs, cells expressing CD95L message and protein were scarce and comprised scattered lymphocytes, rare nonlymphoid cells, and a subset of epithelioid endothelial cells. Surprisingly, a subset of plasma cells turned out to be the most prominent producers of CD95L, matching the reports on CD95L in myeloma cells. CD95L+ plasma cells were most numerous in the mucosa-associated lymphoid tissue. This also applied to acquired mucosa-associated lymphoid tissue in chronic gastritis in which CD95L+ plasma cells were found scattered in the lamina propria. Our data suggest that plasma cells as yet may be neglected modulators of immune responses.
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PMID:CD95 ligand (CD95L) in normal human lymphoid tissues: a subset of plasma cells are prominent producers of CD95L. 991 33

Our knowledge in immunology has been dramatically increased by several excellent investigations elucidating the role of the Fas (Apo-1/CD95) receptor/ligand (FasL) system in complex immunological processes such as the acquisition of self tolerance in T cells, progression of autoimmunity, clonal deletion of activated T cells, B-cell regulation and the establishment of "immune privileged" sites such as testis or retina. In addition to these regulatory immunological activities, Fas/FasL interaction was also shown to participate in active defense mechanisms of the host against infected or transformed cells thereby inducing apoptosis in target cells. However, the same mechanism seems also to be part of an escape strategy utilized by tumor cells in various neoplastic malignancies of both hematopoetic as also non-hematopoetic origin. We ourselves were able to demonstrate that neoplastic plasma cell lines, as well as native malignant myeloma cells constitutively express FasL mRNA and protein. The FasL molecule is functionally active and able to induce programmed cell death in Fas sensitive target T cells in vitro. These target T cells were protected from programmed cell death by preincubation of T cells with a Fas-blocking monoclonal antibody (mAb) or of myeloma cells with a FasL-neutralizing mAb. respectively. Furthermore, overexpression of the caspase inhibitor, cowpoxvirus protein CrmA, also protected target T cells from being killed by myeloma cells, identifying Fas/FasL mediated signaling as the effector pathway utilized by malignant plasma cells. Our observations strongly suggest the engagement of Fas/FasL interaction in the escape strategy of this malignancy. The molecular basis of this evasive mechanism differs in essential respects from those described in melanoma, lung cancer, hepatocellular carcinoma, or astrocytoma, since downregulation of Fas or instrinsic insensitivity towards Fas-mediated signaling were not prerequisites for the occurrence of this phenomenon in Fas-sensitive multiple myeloma cell lines. However, myeloma cell lines resisted cocultivation with FasL-expressing target T cells in vitro. The aim of this review is to discuss the role of Fas/FasL interaction in the establishment of malignant disease, in the light of our findings on myeloma cells and also by drawing upon similar observations of other investigators on different kinds of tumor cells and cell lines and further to consider its possible relevance in formulating novel approaches to cancer therapy.
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PMID:On the role and significance of Fas (Apo-1/CD95) ligand (FasL) expression in immune privileged tissues and cancer cells using multiple myeloma as a model. 992 38

Recombinant human hematopoietic growth factors are widely used in the treatment of multiple myeloma (MM) especially due to the increasing role of autologous blood stem cell transplantation (ABSCT). We report a patient with MM in whom rapid extramedullary progression of disease was observed during stem cell mobilization with G-CSF. In 56-year-old man with relapsing IgG lambda MM myeloablative therapy with ABSCT was planned 2 years after diagnosis. G-CSF is increasing doses was used for mobilization. Ten days after the start of G-CSF therapy 2 extramedullary (subcutaneous) myeloma infiltrates appeared. For the second mobilization high dose cyclophosphamide and VP-16 with subsequent G-CSF was used. During the time of chemotherapy tumour infiltrates disappeared, however, after one week of G-CSF treatment rapid progression of disease with the formation of multiple extramedullary infiltrates occurred and the patient died in June 1996. Small pieces of subcutaneous tumour infiltrates were removed at autopsy and immediately frozen in liquid nitrogen. Using the panel of specific antibodies the expression of cytokine receptors (IL-1, 2, 3, 6, 7, 8, 10, SCF, gp130, G-CSF, GM-CSF, EPO) and Fas, Pgp and 24-34 kD multidrug resistance-associated protein were examined. However, no expression of cytokine receptors on tumor cells was found. On the contrary, high positivity of surface MDR associated proteins was observed.
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PMID:[Progression of multiple myeloma during treatment with recombinant G-CSF and absence of G-CSF and IL-6 cell surface receptors on malignant cells]. 992 31

Interleukin 6 (IL-6) is the major survival factor for myeloma tumor cells and induces signaling through the STAT proteins. We report that one STAT family member, Stat3, is constitutively activated in bone marrow mononuclear cells from patients with multiple myeloma and in the IL-6-dependent human myeloma cell line U266. Moreover, U266 cells are inherently resistant to Fas-mediated apoptosis and express high levels of the antiapoptotic protein Bcl-xL. Blocking IL-6 receptor signaling from Janus kinases to the Stat3 protein inhibits Bcl-xL expression and induces apoptosis, demonstrating that Stat3 signaling is essential for the survival of myeloma tumor cells. These findings provide evidence that constitutively activated Stat3 signaling contributes to the pathogenesis of multiple myeloma by preventing apoptosis.
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PMID:Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. 1002 75

Expression density and function of Fas (APO-1/CD95) on malignant B-cells, an antigen thought responsible for abnormal tumor biology, remains to be fully understood. Fifty-five cases with B-cell neoplasms of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), B-cell malignant lymphoma (ML), and myeloma (MM) were studied for qualitative and quantitative expression and function of Fas using flow cytometry and annexin-V staining methods. Fas expression was flow cytometrically unimodal with heterogeneous density and showed quantitatively characteristic features among different diseases; weak in ALL, faint in CLL, moderate in HCL, and strong in ML, respectively. Not only full-length but also alternatively spliced truncated mRNAs were detected even in leukemic B-cells with qualitatively faint or negative Fas, and then band density of the former transcripts by RT-PCR was correlated to the Fas protein expression level. Short-term culture of freshly isolated cells gave rise to increases of Fas density and susceptibility for apoptosis, suggesting that the mRNA and inducible Fas are functional at least in vitro. These results show that Fas is a biological marker for characterizing B-cell neoplasms reflecting various stages of B-cell ontogeny and may have clinical utility as a therapeutic strategy.
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PMID:Qualitative and quantitative characterization of Fas (APO-1/CD95) on leukemic cells derived from patients with B-cell neoplasms. 1007 Nov 31


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