UMLS:C0026764 - FACTA Search

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)

In the present study, we aimed to identify distinct structural and numerical chromosomal aberrations in peripheral blood B cells of patients with myeloma and monoclonal gammopathy of undetermined significance (MGUS), which reflect changes thought to occur at different stages of the disease process. Peripheral blood from 12 patients with multiple myeloma and three patients with MGUS was investigated for the occurrence of retinoblastoma-1 gene deletions, p53 gene deletions and numerical aberrations demonstrated previously to be present in the patients' bone marrow CD138+ cells. By combining immunocytochemical staining for light chains and interphase fluorescence in situ hybridization (FISH), aberrant light-chain +ve cells were detected in the circulating CD19+ cell fraction. Each kind of chromosomal change present in the myeloma tumour cells was found to be shared by a small fraction of CD19+ cells (0.1-1.8%; median 0.36%, n = 6). In one MGUS patient, aberrant cells could be identified with a frequency of 0.34% within the CD19-sorted cell fraction. Clonotypic cells were detected with a frequency of 0.01-0.07% of peripheral blood nucleated cells by m-RNA in situ hybridization with patient-specific probes in three investigated patients. These results provide evidence that the circulating clonotypic B cells are closely related to the malignant plasma cells in myeloma and MGUS.
...
PMID:Chromosomal aberrations are shared by malignant plasma cells and a small fraction of circulating CD19+ cells in patients with myeloma and monoclonal gammopathy of undetermined significance. 1206 Jan 20

Multiple myelomas often occur in elderly people with complications due to aging. A 54-year-old man was first admitted with cerebral infarction, and multiple myeloma (IgG kappa, stage IIIA) occurred in November 1989 that was followed by partial remission after chemotherapy. The karyotype of the bone marrow cells was 46, XY, and no p53 gene mutations were detected by polymerase chain reaction and single-strand conformation polymorphism analysis. Chemotherapy (melphalan 10 mg, vindesine 3 mg, ranimustine 150 mg, prednisolone 60 mg for 4 days) was performed in February 1999 because of aggravation of the myeloma. After daily subcutaneous injection of 50 micrograms of nartograstim for six days to treat neutropenia, soft tissues around the right eye were swelled gradually without redness, accompanied by elevation of the serum creatine-kinase concentration. The swelling disappeared, and the enzyme level normalized after discontinuation of nartograstim. In July, on the sixth day of daily subcutaneous injection of 75 micrograms of filgrastim after the same chemotherapy, similar swelling of the soft tissues around the left eye became evident, and again this proved reversible. In July 2000, 40 mg of dexamethasone was infused, and after 5-day subcutaneous-injection of 75 micrograms of filgrastim daily, the right subclavicular soft tissue became swollen. He died of myocardial infarction, and autopsy revealed infiltration of myeloma cells into the right subclavicular muscle and bone marrow packed with myeloma cells. This case suggests that myeloma cells can proliferate and infiltrate into soft tissues on exposure to granulocyte-colony stimulating factors.
...
PMID:[A case of multiple myeloma with infiltration into skeletal muscle after injections of a granulocyte-colony stimulating-factor]. 1218 9

We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.
...
PMID:Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. 1239

Multiple myeloma is a malignant proliferation of plasma cells which fail to undergo apoptosis. To understand events associated with lack of apoptosis in these cells, we studied effect of antisense p53 gene transduction in a multiple myeloma cell line, ARH77. Adeno-associated virus was used as a vector to introduce p53 cDNA in an antisense orientation driven by a herpes virus thymidine kinase promoter. We observed, that an antisense p53 (p53as) transduced cell line showed marked reduction in p53 mRNA and protein expression and increased growth when compared to the control cell lines transduced with neomycin-resistance gene or untransduced cells. There was a concomitant up-regulation of bcl-2 expression by over five-fold in p53as-transduced cells compared with controls; while there was no significant change in expression of c-myc and IL-6, genes implicated in myeloma growth. We measured apoptosis in the transduced cells by DNA end-labeling reaction which revealed decrease in apoptosis from 15.6% in control cells to 1.6% in p53as-transduced cells. Additionally, the p53as cells over expressing bcl-2 also showed resistance to killing by dexamethasone. In summary, our data demonstrates that loss of p53 function leads to myeloma cell progression and resistant phenotype through bcl-2-related mechanisms.
...
PMID:Antisense p53 transduction leads to overexpression of bcl-2 and dexamethasone resistance in multiple myeloma. 1247 55

Overexpression of Bcl-2 in myeloma cells results in resistance to drugs such as dexamethasone (DEX), adenovirus-mediated delivery of p53 (Ad-p53), and paclitaxel (TAX), which work through the intrinsic apoptotic pathway. Bcl-2 antisense oligodeoxynucleotides (Bcl-2-ASO) have been shown to induce apoptosis in cancer cells, as a single agent or, better, in combination with chemotherapy. We hypothesized that down-regulation of Bcl-2 by Bcl-2-ASO will sensitize drug-resistant myeloma cells to undergo apoptosis. In this paper we report a detailed time/dose study of the effect of Bcl-2-ASO on myeloma cells with varying levels of Bcl-2. Treatment of myeloma cells expressing relatively low levels of Bcl-2 with Bcl-2-ASO resulted in a substantial apoptosis concomitant with a substantial depletion of Bcl-2 protein. Maximal apoptosis was observed at 5 to 10 microg/mL Bcl-2-ASO, following 4 days of treatment. Down-regulation of Bcl-2 and apoptosis were time and dose dependent and were sequence specific. In these cell lines, apoptosis was accompanied by activation of caspase-9 and caspase-3 and by release of cytochrome c to the cytosol. In contrast, high Bcl-2-expressing myeloma cells were practically resistant to Bcl-2-ASO. Most important, however, pretreatment of myeloma cells expressing high levels of Bcl-2 with Bcl-2-ASO increased the extent of DEX-, TAX-, and Ad-p53-induced apoptosis from 10%-20% to 70%-90%. Increased apoptosis was accompanied by additional decrease in Bcl-2 protein. Similar results for down-regulation of Bcl-2 and apoptosis were obtained with freshly isolated myeloma cells. These data support development of clinical trials with combinations of Bcl-2-ASO and DEX, TAX, or Ad-p53 in the treatment of refractory myeloma patients.
...
PMID:Potentiation of dexamethasone-, paclitaxel-, and Ad-p53-induced apoptosis by Bcl-2 antisense oligodeoxynucleotides in drug-resistant multiple myeloma cells. 1252 96

Arsenic trioxide (ATO) has been shown to induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells concomitant with down-regulation of the PML-RARalpha fusion protein, a product of the t(15:17) translocation characteristic of APL leukemic cells. However, ATO is also a potent inducer of apoptosis in a number of other cancer cells lacking the t(15:17) translocation. The exact mechanism of ATO-induced apoptosis in these cells is not yet clear. We tested the effect of ATO on 7 myeloma cell lines with varying p53 status and report that in cells with mutated p53, ATO induced rapid and extensive (more than 90%) apoptosis in a time- and dose-dependent manner concomitant with arrest of cells in G(2)/M phase of the cell cycle. Myeloma cells with wild-type (wt) p53 were relatively resistant to ATO with maximal apoptosis of about 40% concomitant with partial arrest of cells in G(1) and up-regulation of p21. The use of caspase blocking peptides, fluorescence-tagged caspase-specific substrate peptides, and Western immunoblotting confirmed the involvement of primarily caspase-8 and -3 in ATO-induced apoptosis in myeloma cells with mutated p53 and primarily caspase-9 and -3 in cells expressing wt p53. We also observed up-regulation by ATO of R1 and R2 APO2/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors. Most important, however, we observed a synergy between ATO and APO2/TRAIL in the induction of apoptosis in the partially resistant myeloma cell lines and in myeloma cells freshly isolated from myeloma patients. Our results justify the use of the combination of these 2 drugs in clinical setting in myeloma patients.
...
PMID:Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. 1253 93

Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.
...
PMID:Molecular sequelae of histone deacetylase inhibition in human malignant B cells. 1253 99

Multiple myeloma (MM) is characterized by a multistep process of tumorigenesis involving genes that control cell cycle progression. The prevalence and clinical implications of p53, p21, HDM-2, p27, and cyclin E immunoreactivity in MM patients, however, have not been fully elucidated. We evaluated the immunoreactivity (IR) for p53, p21, HDM-2, p27, cyclin E, and Ki-67 in bone marrow biopsies from 48 patients. In 34 (70.8%) cases, TP53 gene mutations and HDM-2 gene amplification were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and Southern blot densitometric analyses in the corresponding bone marrow aspirates. Nineteen (39.6%) biopsy specimens exhibited > or =10% neoplastic cells immunoreactive for p53, 23 (47.9%) for p21, 28 (58.3%) for HDM-2, 29 (60.4%) for cyclin E, and 16 (33.3%) for Ki-67; 23 (47.9%) tumors had > or =50% neoplastic cells immunoreactive for p27. TP53 gene mutations in exons 5 through 8 were detected in 3 (8.8%) cases, whereas none exhibited HDM-2 gene amplification. In the cases bearing a wild-type TP53 gene, no association was found between p53 accumulation and HDM-2 or p21 IR. The same cases had been previously investigated for the presence of the t(11;14) translocation and cyclin D1 IR; interestingly, a significant inverse correlation between cyclin D1 and p27 or cyclin E IR was noted. In addition to clinical stage and Bartl's histologic stage and grade, p53 accumulation was significantly associated with survival, and it maintained its prognostic significance in a multivariate analysis adjusted for age, clinical stage, and relapse. Our data suggest that the immunohistochemical evaluation of p53 IR in bone marrow biopsies may represent an adjunct in MM patient prognostication.
...
PMID:Cell cycle regulators in multiple myeloma: prognostic implications of p53 nuclear accumulation. 1260 65

Despite the advances in our knowledge of myeloma cell biology, our understanding of myeloma pathogenesis is still incomplete. In this review, we present a summary of the cellular and molecular aspects of B-cell development and immunoglobulin (lg) gene rearrangement which have been important in defining the characteristics of the myeloma plasma cell (MPC). The PMC has undergone variable gene recombination, somatic hypermutation and isotype switching, and is therefore at a postgerminal center stage of development. The finding of preswitch clonal cells and isotype variants have raised interesting questions about the cell of origin of myeloma, for which no conclusive data is as yet available. However much information has been obtained about the chromosomal and genetic aberrations in myeloma, including monosomy 13, Ig heavy chain (IgH) switch region translocations, numerical abnormalities and a multitude of heterogeneous changes. A variety of techniques have been developed to overcome the insensitivity of conventional karyotyping, utilizing molecular cytogenetic strategies ranging from the delineation of precise loci by fluorescent in situ hybridization, a more "global" assessment of the genome by multicolor spectral karyotyping, to the quantitation of chromosomal material of specific origin by comparative genomic hybridization. Whether the abnormalities detected represent oncogenic insults, are involved in disease progression or are simply "by-products" of genetic instability is still unclear. For IgH translocations, the role of candidate genes such as Cyclin D1 and FGFR3 has been studied extensively by quantitating their expression and assessment of their oncogenicity (e.g. for FGFR3) in animal models. The significance of other aberrations such as c-myc, ras and p53 has also been investigated. With the advent of oligonucleotide microarrays, the expression of thousands of genes can be efficiently examined. So far, this approach seems promising in defining subgroups of different disease behavior, and may highlight specific genes and molecular mechanisms which are important in myeloma pathogenesis.
...
PMID:The biology and cytogenetics of multiple myeloma. 1261 99

Multiple myeloma (MM) is an incurable malignant neoplasm affecting terminally differentiated B-cells. It derives from post-germinal center B-cells and develops as a result of multistep tumorigenic events, because approximately one third of all MM cases have a history of preceding monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma. MM terminates in the formation of extramedullary invasion or in secondary plasma cell leukemia. To account for this clinical experience, investigators have found that intrinsic chromosomal instability followed by complex chromosomal translocations/deletions plays a crucial role in the development from MGUS to MM. Representative aberrations include chromosomal rearrangements involving 14q32 loci and deletion at the long arm of chromosome 13. Contributing to the progression of MM itself are genomic instability and altered methylation of the specific gene promoters. The former results in activation of specific oncogenes such as RAS and FGFR3 or in inactivation of p53, and the latter results in inactivation of tumor suppressor genes, including p16. An accurate understanding of each of these molecular events should help clarify the development of specific molecular targeting therapies based on the differences in dysfunctional signaling pathways found in the cells of all MM patients.
...
PMID:Multistep tumorigenesis of multiple myeloma: its molecular delineation. 1273 62

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>