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)

As at present only a long-term follow-up can fully determine whether monoclonal gammapathies of undetermined significance (MGUS) will evolve into multiple myeloma (MM), this study attempted to identify other variables connected with the amount of monoclonal component (MC), generally considered as the most reliable marker of malignant evolution. Thirty-four MGUS subjects showing a high MC (> or = 15.0 g/l) but without clinical evidence of MM (MGUS group b), were characterized for their phenotypic and genotypic profile by comparing them either with 40 MM patients or with 24 subjects affected by a benign form of monoclonal gammapathy (MGUS group a) according to the standard criteria. In addition to the usual laboratory markers, the levels of expression of a panel of CD membrane subsets were measured on B and T lymphocytes. Also, the serum level of the p53 mutant protein and the structural alterations of the c-myc oncogene were evaluated. The results show that for MGUS group b patients, an increased M-protein was accompanied by significantly increased levels of peripheral blood CD3+ T cells and oncogenetic aberrations in c-myc. Since a high serum MC level seems to indicate a greater likelihood of malignant transformation for MGUS patients, these findings suggest that this relationship may be a result of the concomitant alterations observed at a phenotypic and genotypic level. Such alterations may be potentially useful as surrogate markers for the transition of benign to malignant (MM) plasma cell dyscrasia.
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PMID:Phenotypic and genotypic alterations characterize patients bearing plasma cell dyscrasias with a high M-component. 1061 12

Detection of abnormal numbers and/or distribution of bone marrow (BM) plasma cells (PCs) on trephine biopsies can be important in the differential diagnosis of multiple myeloma (MM) and other PC disorders. A variety of immunohistochemical markers can potentially improve the specificity and sensitivity of PC detection on routine histological sections obtained from trephine BM biopsies, but most of them are not completely satisfactory. In this study, we investigated whether the antibody CD138/B-B4, which is an optimal marker for PC detection on BM aspirates by flow cytometry, can be used successfully for the identification of PCs also on formalin-fixed, decalcified biopsies. A series of samples including normal BM [12], MM [65], monoclonal gammopathies of undetermined significance [44], and B-cell lymphoma of various types [94], including B-cell precursor lymphoblastic leukemia [9], lymphoplasmacytoid [17], immunoblastic [14], lymphocytic/CLL [23], hairy cell leukemia [4], large B-cell [8], mantle-cell [3], marginal zone [6] and follicular [10] lymphomas, have been investigated for CD138 expression using a sensitive immunohistochemical technique. Within the BM microenvironment, CD138 was characterized by excellent sensitivity and specificity. Virtually all normal and neoplastic PCs expressed clear-cut membrane CD138 immunostaining, whereas all other cell types did not. All cases of MM, including plasmablastic and leukemic cases, showed strong immunoreactivity. Conversely, all B-cell lymphomas, including all cases characterized by secretive features, lymphoplasmacytoid, and immunoblastic lymphomas, were completely negative. These results demonstrate that CD138 is a highly sensitive and specific marker that is useful for the rapid and precise localization of normal and neoplastic PCs on routine BM sections. In addition, because of its clear-cut cell membrane localization, CD138 can be used successfully in double-marker immunostaining reactions to evaluate precisely nuclear prognostic markers such as Ki67 and p53 in MMs.
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PMID:CD138/syndecan-1: a useful immunohistochemical marker of normal and neoplastic plasma cells on routine trephine bone marrow biopsies. 1061 61

It has been reported that the activation of multiple myeloma (MM) cells by CD40 induces proliferation, growth arrest, and apoptosis. To determine whether the biologic sequelae of CD40 activation in MM cells depends on p53 function, we identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and the HS Sultan (tsp53Y163H) MM cell lines. These cells were then used as a model system of inducible wtp53-like function because wild-type-like p53 is induced at permissive (30 degrees C) but not at restrictive (37 degrees C) temperatures. Using p21-luciferase reporter assays, we confirmed that CD40 induces p53 transactivation in RPMI 8226 and HS Sultan cells cultured under permissive, but not restrictive, conditions. Furthermore, CD40 activation of these MM cells under permissive, but not restrictive, temperatures increased the expression of p53 and p21 mRNA and protein. Importantly, CD40 activation induced the proliferation of RPMI 8226 and HS Sultan cells at restrictive temperatures and growth arrest and increased subG1 phase cells at permissive temperatures. These data confirmed that CD40 activation might have distinct biologic sequelae in MM cells, depending on their p53 status.
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PMID:CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines. 1064 20

Recently, several advances have been made in understanding the pathogenesis of multiple myeloma. Increasing evidence favours a pre-switched, but somatically mutated B-cell as myeloma stem cell to give rise to the malignant clone. Deletions of the p53-gene, partial or total loss of chromosome 13 and rearrangements of band 14q32 and 11q13 are frequently found in multiple myeloma, and were shown to harbour prognostic significance. Presence or absence of distinct chromosomal aberrations may guide selection of treatment strategies in the future. Although melphalan/prednisolone remains the standard of myeloma treatment in elderly patients, significant improvement has been achieved in antimyeloma and in supportive therapy. High dose therapy with autologous stem cell transplantation enhances survival in younger patients and several trials are ongoing to substantiate these results. The effects of interferon maintenance treatment on overall survival is significant in metaanalysis, although the gain achieved is limited. Newer treatment strategies--targeting the molecular level--have just entered clinical trials, and may further improve outcome of myeloma patients.
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PMID:Multiple myeloma: an update on biology and treatment. 1067 51

Recently, a working-model of a stepwise malignant transformation in the molecular pathogenesis of multiple myeloma (MM) was proposed, involving the tumor suppressor gene TP53 and retinoblastoma gene (RB1) as prominent components of cell cycle control. To further define the role of TP53 and RB1 in disease progression, we retrospectively analyzed by fluorescence in situ hybridization (FISH) cytological material from 16 patients who underwent sequential bone marrow biopsies during the course of their disease. For TP53, no deletions were detected at presentation or during follow-up. It is possible that the patients reported here represent a subset with relatively long survival, and therefore did not demonstrate the TP53 deletions that had been reported in patients with a very poor prognosis. For RB1, monoallelic deletion was demonstrated in nine patients. In each case, the deletion appeared already in the first biopsy analyzed. The presence of a deletion did not affect the rate of tumor progression or the length of follow-up, and thus prognosis. Monoallelic deletions of RB1 appear to be a frequent and early event in the pathogenesis of MM, without obvious relevance for disease progression.
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PMID:Multiple myeloma: monoallelic deletions of the tumor suppressor genes TP53 and RB1 in long-term follow-up. 1070 Aug 68

BACKGROUND: Approximately 25% of patients with monoclonal gammopathy of undetermined significance (MGUS) eventually develop multiple myeloma (MM) or a related plasma cell disorder that is universally fatal. In this report, we examine the changes that occur in the clonal plasma cell that are likely to be important in the progression of MGUS to active myeloma. METHODS: Studies that investigate the mechanisms involved in the multistep pathogenesis of monoclonal gammopathies are reviewed. Cytokines such as IL-6 and IL-1-beta, adhesion molecules, viruses, and oncogenes including ras, bcl-2, Rb, and p53 are discussed. RESULTS: IL-1-beta is produced by plasma cells from virtually all MM patients but is undetectable in most MGUS patients. IL-1-beta has potent osteoclast activating factor activity, can increase the expression of adhesion molecules, and can induce paracrine IL-6 production. The increased production of adhesion molecules could explain why myeloma cells are found predominantly in the bone marrow. Subsequently, these "fixed" monoclonal plasma cells could now stimulate osteoclasts through the production of IL-1-beta and paracrine generation of IL-6 resulting in osteolytic disease. With continued progression of the myeloma, the monoclonal plasma cells may later acquire the ability to produce IL-6 in an autocrine fashion that will be manifested clinically by an elevated labeling index. CONCLUSIONS: A better understanding of the progression of MGUS to myeloma may lead to novel therapeutic strategies to prevent the development of MM.
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PMID:Biology of the Transition of Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma. 1076 Oct 54

DM650, a soluble human IL-6Ralpha mutant with mutation of C277D/H280I, was previously shown to exhibit an antagonism to IL-6, which resulted in growth-inhibition of human multiple myeloma cell line AF-10 autocrining as the growth-stimulating factor. We investigated here the nature of the growth inhibition by examining cell apoptosis. Flow-cytometric analysis of the DNA fragmentation demonstrated that 7.2% of the AF-10 cells were apoptotic after 24 h of treatment with DM650. The constitutive gene expression of bcl-2 in AF-10 cells indicated that apoptosis suppressed by IL-6 was independent of bcl-2 regulation. The altered gene expression of c-myc and p53 suggested that a novel apoptosis pathway, other than that suppressed by IL-6, might be triggered by a complex of DM650 and IL-6.
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PMID:Study on the growth inhibition of human multiple myeloma cells by an IL-6Ralpha mutant. 1077 37

A novel therapeutic potential for acute promyelocytic leukemia using arsenic trioxide (As(2) O(3) ) has been reported. Recent in vitro studies demonstrated that As(2) O(3) effectively inhibits the growth of some cell lines derived from patients with malignant lymphoma, chronic lymphocytic leukemia and multiple myeloma. Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T-cell origin caused by human T-cell leukemia virus type-I (HTLV-I) the prognosis of which still remains very poor. A possible role of As(2) O(3) for the treatment of ATL is demonstrated from evidence that As(2) O(3) significantly inhibits the growth of HTLV-I infected T-cell lines and induces apoptosis in fresh ATL cells at clinically achievable concentration of the agent. The growth inhibition of As(2) O(3) treated HTLV-I infected T-cell lines was induced by both apoptosis and G(1) phase accumulation. Cleaved bcl-2 protein and an enhanced expression of bak protein in the cells were coincidentally observed during As(2) O(3) treatment. A broad spectrum caspase inhibitor, z-Val-Ala-DL-Asp-fluoromethylketone inhibited the apoptosis induced by As(2) O(3). Increased expression of p53, Cip1/p21 and Kip1/p27, and dephosphorylation of retinoblastoma protein (pRb) were detected in the As(2) O(3) treated cells. In conclusion, As(2) O(3) might become a new therapeutic tool in the treatment of ATL as As(2) O(3) induces apoptosis by destruction of the bcl-2 protein and enhancement of the bak protein production proceeding to activate caspases, and also induces G(1) phase accumulation by enhancement of p53, Cip1/p21, Kip1/p27 and dephosphorylation of pRb to HTLV-I infected T-cell lines.
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PMID:Arsenic trioxide and the growth of human T-cell leukemia virus type I infected T-cell lines. 1104 29

Because there is no known genetic abnormality common to all patients with myeloma, it is important to understand how genetic heterogeneity may lead to differences in signal transduction, cell cycle, and response to therapy. Model cell lines have been used to study the effect that mutations in p53 and ras can have on growth properties and responses of myeloma cells. The U266 cell line has a single mutant p53 allele. Stable expression of wild-type (wt) p53 in U266 cells results in a significant suppression of interleukin (IL)-6 gene expression and in the concomitant suppression of cell growth that could be restored by the addition of exogenous IL-6. Expression of wt p53 also leads to cell cycle arrest and protection from doxorubicin (Dox)- and melphalan (Mel)-induced apoptosis. The addition of IL-6 resulted in cell cycle progression and blocked p53-mediated protection from apoptosis. ANBL6 is an IL-6-dependent cell line that is sensitive to dexamethasone (Dex), Dox, and Mel. IL-6 is able to protect ANBL6 cells from Dex- and Mel- but not Dox-induced apoptosis. To study the effect of an activating mutation in ras, the ANBL6 cell line transfected with either a constitutively activated N- or K-ras gene was used. Both N-ras12 and K-ras12 genes were able to protect ANBL6 cells from apoptosis induced by Dex, Dox, and Mel. These data show that changes in ras or p53 can alter the myeloma cell response to IL-6 and demonstrate that the genetic background can alter therapeutic responses.
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PMID:Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. 1105

Multiple myeloma (MM) is an incurable disease; therefore, there is a need for new modalities of treatment for this disease. We designed a study to test the sensitivity of MM cell lines, freshly isolated myeloma cells, and CD34(+) hematopoietic progenitor cells to adenovirus-mediated delivery of wild-type p53 (Ad-p53). Replication-deficient Ad-p53, previously used in phase I-II clinical trial for treatment of patients with solid tumors, was used in this study. Myeloma cells from seven MM cell lines with mutated or w.t. p53 and varying expression of bcl-2 were used. Fresh myeloma cells (CD38(bright)CD45(-)) and fresh CD34(+) hematopoietic stem cells and CD34(-) cells were purified by flow sorting of apheresis collections of MM patients undergoing high-dose chemotherapy and stem cell rescue. The effect of Ad-p53 on colony-forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit erythroid (BFU-E) colony formation in methylcellulose was tested on purified CD34(+) and CD34(-) cells to evaluate bone marrow toxicity. Myeloma cells from cell lines, or freshly isolated myeloma cells, were sensitive to Ad-p53 only if they had mutated p53 and had low expression of bcl-2. CD34(+) cells were resistant to Ad-p53-mediated apoptosis, and CFU-GM and BFU-E colony formation was not affected by treatment with Ad-p53.Ad-p53 is a potent inducer of apoptosis in MM cell lines and in freshly isolated myeloma cells expressing low levels of bcl-2. Ad-p53 is not overtly cytotoxic to normal hematopoietic stem cells or normal lymphocytes; therefore, it could be considered for a phase I clinical trial of MM patients with mutated p53.
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PMID:Adenovirus-mediated delivery of p53 results in substantial apoptosis to myeloma cells and is not cytotoxic to flow-sorted CD34(+) hematopoietic progenitor cells and normal lymphocytes. 1114 57


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