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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-apoptotic pathways play a central role in the survival of multiple myeloma cells. The contribution of PI3-kinase and Akt kinase in mediating myeloma cell survival is well established although the role of glycogen synthase kinase-3 (GSK3) is less defined. In this study we determined the contribution of GSK3 in growth regulation of myeloma cells. We treated six different multiple myeloma cell lines with a Thiadiazolidinone (TDZD), a non-competitive inhibitor of GSK3 and determined its effects on proliferation and apoptosis. In addition we determined the activation of forkhead transcription factors (FOXO) in response to TDZD. TDZD inhibited proliferation and induced apoptosis of all myeloma cell lines. TDZD was also effective in inducing apoptosis of primary myeloma cells whereas CD34 positive normal hematopoietic cells were protected from apoptosis. Furthermore, TDZD-mediated inhibition of GSK3 resulted in dephosphorylation and activation of FOXO3a. In primary myeloma cells FOXO transcription factors were highly phosphorylated where as the levels of GSK3 phosphorylation was quite low. The levels of the pro-apoptotic proteins Fas ligand (FasL) and IkappaBalpha increased after treatment with TDZD in myeloma cell lines. These studies provide the basis for further testing of GSK3 inhibitors in the clinical setting.
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PMID:Growth control of multiple myeloma cells through inhibition of glycogen synthase kinase-3. 1872 64

Idiotype (Id) protein, secreted by myeloma cells, is a tumor-specific antigen. Id-based immunotherapy has been explored in patients with myeloma, and results were disappointing. Although previous studies have shown that Id-specific CTLs are able to lyse myeloma cells, it is unclear whether other types of Id-specific T cells, such as type-1 T-helper (Th1) and type-2 T-helper (Th2) cells, are also able to suppress or kill myeloma cells. Using a 5T murine myeloma model, we generated T-cell clones of different subsets and examined their function in the context of myeloma cells. Id-specific CTLs specifically lysed myeloma cells via MHC class I, perforin, and Fas ligand (FasL), and Th1, but not Th2, cells lysed the myeloma cells by FasL-Fas interaction. CTL and Th1 cells also suppressed the growth and function of myeloma cells, whereas Th2 cells promoted the proliferation and enhanced the secretion of Id protein and cytokines by myeloma cells. CTL and Th1, but not Th2, cells were able to eradicate established myeloma in vivo after adoptive transfer. These results show that Id-specific CTL and Th1 are promising effector cells, whereas Th2 provide no protection and may even promote tumor progression in vivo.
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PMID:Roles of idiotype-specific t cells in myeloma cell growth and survival: Th1 and CTL cells are tumoricidal while Th2 cells promote tumor growth. 1892 19

Syndecan is the major transmembrane proteoglycan in cells. Of the four syndecans, syndecan-1 is the dominant form expressed in multiple myeloma and is an indicator of poor prognosis. In the current study, we observed that early TRAIL-induced apoptotic processes were accompanied by cleavage of syndecan-1 intracellular region, and explored the possibility whether removal of syndecan-1 promotes apoptotic processes. We found that syndecan-1 knockdown by specific small interfering RNA in multiple myeloma enhanced TRAIL-induced apoptosis, even though the expression of TRAIL receptors and several apoptosis-associated molecules was unaffected. The enhanced TRAIL-mediated apoptosis in syndecan-1-deficient cells was not due to a decrease in surface heparan sulfate or a reduction in TRAIL receptor endocytosis. The increase in TRAIL-induced cell death was accompanied by an elevated caspase-8 activation and an enhanced formation of death-inducing signaling complexes, which could be attributed to an increased expression of TRAIL receptor O-glycosylation enzyme in syndecan-1-deficient cells. We also found that in H9 lymphoma and Jurkat cells, knockdown of the predominant syndecan member also led to an increase in Fas ligand-induced apoptosis. Our results demonstrate that syndecan plays a negative role in death receptor-mediated cell death, suggesting potential application of syndecan downregulation in the treatment of myeloma in combination with TRAIL.
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PMID:Removal of syndecan-1 promotes TRAIL-induced apoptosis in myeloma cells. 2230 10

Multiple myeloma is a common hematological malignancy that leads to the occurrence of bone lesions. The combination of traditional cytotoxic and novel agents is usually taken to treat multiple myeloma-related bone diseases. However, the curative effect is not very satisfactory. Stem cell-based therapy has been recently introduced and investigated, which represents a new frontier in the treatment of multiple myeloma. In a recent interesting study, Dr Atsuta and colleagues provide a new insight into the effects of mesenchymal stem cells on multiple myeloma via Fas/Fas ligand pathway, which rekindles the fire of hope for those patients suffering from multiple myeloma.
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PMID:A new hope for patients suffering from multiple myeloma. 2402 90

Multiple myeloma is a malignant disorder characterized by bone marrow proliferation of plasma cells and by overproduction of monoclonal immunoglobulin detectable in the sera (M-spike). Anemia is a common complication of multiple myeloma, but the underlying pathophysiological mechanisms have not been completely elucidated. We aimed to identify the different determinants of anemia using the Vk*MYC mouse, which spontaneously develops an indolent bone marrow localized disease with aging. Affected Vk*MYC mice develop a mild normochromic normocytic anemia. We excluded the possibility that anemia results from defective erythropoietin production, inflammation or increased hepcidin expression. Mature erythroid precursors are reduced in Vk*MYC bone marrow compared with wild-type. Malignant plasma cells express the apoptogenic receptor Fas ligand and, accordingly, active caspase 8 is detected in maturing erythroblasts. Systemic iron homeostasis is not compromised in Vk*MYC animals, but high expression of the iron importer CD71 by bone marrow plasma cells and iron accumulation in bone marrow macrophages suggest that iron competition takes place in the local multiple myeloma microenvironment, which might contribute to anemia. In conclusion, the mild anemia of the Vk*MYC model is mainly related to the local effect of the bone marrow malignant clone in the absence of an overt inflammatory status. We suggest that this reproduces the initial events triggering anemia in patients.
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PMID:Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma. 2571 6

Multiple myeloma (MM) is a malignant proliferation of plasma cells in which dysregulation of programmed cell death (apoptosis) is responsible for tumor cell expansion. However some phenotypic and functional alterations of T cells in MM patients have been reported, that also can influence the plasma cell growth. The aim of the study was to assess some aspects of T lymphocyte apoptosis in MM to obtain a better understanding of the changes in the immune system in this disease. Flow cytometry was used to analyze the expression of two main regulators of apoptosis: the pro-apoptotic Fas antigen and the anti-apoptotic protein BCL-2 in patients with untreated MM and in healthy controls. ELISA was used to determine soluble Fas ligand (sFasL) serum levels in patients and control groups. We detected statistically significant higher Fas expression in patients than in controls both on CD4 and CD8 lymphocytes, but no differences in BCL-2 expression by these cells. The sFasL level was statistically significant lower in patients than in controls. Our results indicate that T cells in MM are controlled by up-regulation of Fas. The Fas/FasL system induces the killing of T cells expressing Fas antigen, what could account for the incapability of the immune system to protect host against tumor expansion.
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PMID:Short Communication: Expression of Apoptosis Regulating Factors on T Lymphocytes in Multiple Myeloma Patients. 2740 96


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