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)

Gaucher-like cells have occasionally been described in various haematological malignancies including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma (MM) and chronic myelogenous leukaemia (CML). A special type of this phenomenon is crystal-storing histocytosis or the so-called pseudo-pseudo Gaucher cells (PPGC) in which crystalline protein storage in macrophages is induced by paraproteinemia. Here we describe a 54-year-old man with an initial suspicion of Gaucher disease and monoclonal IgA gammopathy in whom a correct diagnosis of lymphoplasmacytic lymphoma (LPL) with massive infiltration of bone marrow and spleen by PPGC was confirmed by immunological, ultrastructural and molecular characterisation. The activity of leukocyte beta-glucocerebrosidase was only slightly elevated (7.3 nmol/mg protein/1 h) which ruled out the diagnosis of classic Gaucher's disease. The patient received two courses of CHOP without improvement and anti-CD20 monoclonal antibody (rituximab) with only temporary stabilisation. Subsequently, he underwent splenectomy because of prolonged severe pancytopenia and a suspicion of hypersplenism. After splenectomy significant haematological improvement was observed. Following anti-CD20 therapy, changes in immunoprofile and morphology of tumour cells were evident. Before treatment the population of LPL was more divergent, with expression of LCA, CD20, CD38 and CD138. However, after the treatment, there were more mature plasma cells which no longer expressed CD20 antigen-this picture was more consistent with the diagnosis of plasma cell myeloma. Similarly, in the spleen there were no CD-20-positive cells evident. Finally, the patient received two courses of VAD vincristine, doxorubicin, dexamethasone) with further haematological improvement but complete response was not achieved.
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PMID:Lymphoplasmacytic lymphoma with monoclonal gammopathy-related pseudo-Gaucher cell infiltration in bone marrow and spleen--diagnostic and therapeutic dilemmas. 1261 22

The urokinase-type plasminogen activator (uPA) system, which consists of a proteinase (uPA), a receptor (uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration, tissue remodelling, angiogenesis and cell adhesion. Recent findings suggest that malignant plasma cells express uPA and uPAR. The expression of these factors could represent a process by which myeloma plasma cells interact with the bone marrow (BM) environment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing and, possibly, clinical evolution. We evaluated uPAR (CD87) and its soluble form (suPAR) in 49 multiple myeloma (MM) patients and correlated their expression and levels with clinico-biological characteristics of the disease. Flow cytometric analysis demonstrated that CD87 was expressed in all MM patients. High CD87 expression was associated with higher intensity of expression of CD56 (P = 0.038), CD38 (P = 0.058) and CD138 (P = 0.054) and CD45bright positivity (P = 0.014). suPAR levels correlated positively with soluble serum CD138 (P = 0.001), creatinine (P = 0.001), beta2-microglobulin (P < 0.001), disease stage (P = 0.017) and extra-BM involvement (P = 0.002). In the 46 evaluable patients, multivariate analysis showed that high levels of suPAR (P = 0.0214) and disease stage (P = 0.0064) were predictive of extra-BM involvement. In multivariate Cox analysis, 13q deletion (P = 0.0278), high soluble serum CD138 (P = 0.0201) and high suPAR (P = 0.0229) were the only parameters that independently affected survival. We conclude that CD87 is expressed on myeloma plasma cells and that suPAR, which predicts extra-BM involvement and poor prognosis, possibly represents a molecule with a relevant role in the biology of MM.
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PMID:Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patients. 1264 64

We compared gene expression in purified tumor cells from untreated patients with chronic lymphocytic (CLL) (n=24) and newly diagnosed multiple myeloma (MM) (n=29) using the Affymetrix HuGeneFL microarray with probes for approximately 6800 genes. Hierarchical clustering analysis showed that CLL and MM have distinct expression profiles (class prediction). Gene and protein expression (measured by flow cytometry) correlated well for CD19, CD20, CD23, and CD138 in CLL and MM, but not for immunoglobulin light chain, CD38 and CD79b in CLL, or CD45 and CD52 in MM. CLL and MM differentially expressed 18% of 130 apoptosis related genes, suggesting differences in mechanisms of cell survival.
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PMID:The distinct gene expression profiles of chronic lymphocytic leukemia and multiple myeloma suggest different anti-apoptotic mechanisms but predict only some differences in phenotype. 1280 33

Chromosomal translocations involving the immunoglobulin heavy chain gene (IgH) and nonrandom protooncogene loci are the hallmark of genetic alterations found not only in multiple myeloma (MM), but also in premalignant stages of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We studied the frequency of IgH (14q32) rearrangements and their partner chromosomes in 16 Japanese patients with MGUS (13 cases), and SMM (3 cases) by means of interphase double-color fluorescence in situ hybridization (DCFISH) applied to purified plasma cells and using CD138-bead selection. IgH rearrangement was recognized in nine of the patients (56.3%). Protooncogene loci juxtaposed to IgH were identified in seven cases including CCND1 (11q13) in six cases and FGFR3 (4p16) in one. Four out of the six t(11;14)-positive cases showed nuclear staining of the cyclin D1 protein, whereas none of the seven t(11;14)-negative cases did. Moreover, neither MUM1(6p25)-IgH nor MAFB(20q11)-IgH fusion signals were observed. This suggests to us that cyclin D1 deregulation due to the presence of t(11;14) is involved in the early development of plasma cell neoplasms, and that this event alone is not enough for the development of symptomatic myeloma.
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PMID:Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia. 1282 3

Posttransplantation lymphoproliferative disorders (PTLDs) represent a serious complication of solid organ transplantation. This study assessed the molecular histogenesis of 52 B-cell monoclonal PTLDs, including 12 polymorphic PTLDs (P-PTLDs), 36 diffuse large B-cell lymphomas (DLBCLs), and 4 Burkitt/Burkitt-like lymphomas (BL/BLLs). Somatic hypermutation (SHM) of immunoglobulin variable (IgV) genes documented that most monoclonal B-cell PTLDs (75% P-PTLDs, 91.3% DLBCLs, 100% BL/BLLs) derive from germinal center (GC)-experienced B cells. B-cell lymphoma 6 (BCL6) mutations occurred in 25% P-PTLDs, 60.6% DLBCLs, and 75.0% BL/BLLs. A first histogenetic category of PTLDs (31.2% DLBCLs) express the BCL6+/multiple myeloma oncogene-1 protein (MUM1-/+)/CD138- profile and mimic B cells experiencing the GC reaction, as also suggested by ongoing SHM in a fraction of these cases. A second subset of PTLDs (66.7% P-PTLDs and 31.2% DLBCLs) display the BCL6-/MUM1+/CD138- phenotype and mimic B cells that have concluded the GC reaction. A third histogenetic category of PTLDs (25.0% P-PTLDs and 31.2% DLBCLs) shows the BCL6-/MUM1+/CD138+ profile, consistent with preterminally differentiated post-GC B cells. Crippling mutations of IgV heavy chain (IgVH) and/or IgV light chain (IgVL) genes, leading to sterile rearrangements and normally preventing cell survival, occur in 4 DLBCLs and 1 BL/BLL that may have been rescued from apoptosis through expression of Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). Overall, the histogenetic diversity of monoclonal B-cell PTLDs may help define biologically homogeneous categories of the disease.
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PMID:Molecular histogenesis of posttransplantation lymphoproliferative disorders. 1290 42

Syndecan-1 (CD138) mediates myeloma cell adhesion, and loss of syndecan-1 from the cell surface may contribute to myeloma cell proliferation and dissemination and influence the prognosis in patients with multiple myeloma (MM). In order to test this hypothesis, we have evaluated syndecan-1 expression on the surface of malignant plasma cells and soluble forms of syndecan-1 in the serum of 25 newly diagnosed MM patients by flow cytometry and immunosorbent assay. Soluble syndecan-1 levels were significantly higher in MM as compared to controls (P<0.001). Cellular and soluble syndecan-1 was significantly inversely correlated (r=-0.89, P<0.001). The soluble syndecan-1 was significantly higher in non- responders to chemotherapy when compared to responders (P<0.01), and in non- survivors as compared to survivors (P<0.001). In contrast, cellular syndecan-1 expression was significantly lower in non- responders when compared to responders (P<0.01), and in non- survivors as compared to survivors (P<0.05). The levels of soluble syndecan-1 increased from stage I through stage II to stage III, whereas cellular syndecan-1 expression were decreased from high levels in stage III down to a low in stage I, with a statistically significant difference (P<0.01, P<0.05, respectively). There was a significant positive correlation between soluble syndecan-1 and plasma cell count (r=0.079, P<0.001), beta2 microglobulin (r=0.85, P<0.001), serum creatinine (r=0.84, P<0.001), C-reactive protein (r=0.082, P<0.001), alkaline phosphatase (r=0.58, P<0.05) and serum calcium (r=0.77, P<0.01) and a negative correlation with hemoglobin level (r=-0.78, P<0.01), platelets count (r=-0.82, P<0.01) and Albumin level (r=-0.64, P<0.01). Cox regression analysis using soluble syndecan-1 at mean-2SD of the controls could correctly classify patient outcome in 84.0%. The addition of beta2 microglobulin to soluble syndecan-1 increased the predictability of the patients' outcome to 96.7%. We conclude that soluble syndecan-1 levels are negatively correlated to the cellular form and that high levels of soluble syndecan-1 and lower expression of cellular syndecan-1 at diagnosis are negative prognostic factors. Assessment of soluble syndecan-1 and beta2 microglobulin at diagnosis is an independent prognostic system for MM.
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PMID:Syndecan-1 in multiple myeloma: relationship to conventional prognostic factors. 1291 39

Telomeres are specialized nucleoprotein complexes that protect against fusion and degradation of linear chromosomes. Critical shortening of telomeres leads to irreversible cessation of cell division, whereas telomerase elongates telomere sequences to compensate for losses that occur with each round of DNA replication. Continued proliferation of tumor cells requires this enzyme to maintain chromosomal stability and to counteract the cellular mitotic clock. In this study, we evaluated the effect of oligonucleotide N3'-->P5' thio-phosphoramidate (NP), which targets template RNA component, in human multiple myeloma (MM) cell lines and patient MM cells. Fluorescein staining at 24 h confirmed NP uptake in 84.7 and 86.1% of MM.1S cells and MM patient cells, respectively, without any transfection enhancer. High transfection efficiency was observed into both CD138(+) and CD138(-) MM patient cells. Match NP (7S), but not mismatch NP (30S), inhibited telomerase activity in MM.1S cells, U266 cells, and RPMI 8226 cells, as well as in patient MM cells. Moreover, 7S inhibited cytokine-induced telomerase activity in MM.1S cells. 7S treatment-induced progressive telomere shortening was associated with growth inhibition and cell death in MM.1S cells with short telomeres (2.5 kb), but not in U266 cells with long telomeres (9.0 kb), at 56 days of culture. Progressive telomere shortening leading to growth inhibition and cell death in MM.1S cells was associated with up-regulation of p21 and phosphorylation of p53 (Ser-15). These studies, therefore, identify the molecular sequelae of NP oligonucleotide (GRN163) against human telomerase RNA component as a telomerase inhibitor and provide the rationale for the development of telomerase-targeted therapies to improve patient outcome in MM.
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PMID:Effects of oligonucleotide N3'-->P5' thio-phosphoramidate (GRN163) targeting telomerase RNA in human multiple myeloma cells. 1455 2

The methylation status, mutation and expression of RASSF1A, and mutations of RAS and BRAF were studied in 52 patients with multiple myeloma (MM), one plasma cell leukaemia (PCL) patient and four MM-derived cell lines. Aberrant methylation of RASSF1A was found in nine of 32 MM patients and in one of four MM cell lines (U266), where the associated loss of transcription was reversible by demethylation treatment. RASSF1A transcription was further investigated on anti-CD138-sorted plasma cell-enriched bone marrow samples from 10 MM, one PCL and three reactive plasmacytosis patients. While the wild-type RASSF1A transcript was detected in all three reactive plasmacytosis and the PCL samples, we found no detectable wild-type transcripts in six of 10 MM samples studied. In two MM samples, only the non-functional variant transcript was detected, whereas the other four showed loss of transcription. In great contrast to western data, RAS mutations were identified in only four of 31 (13%) MM patients. While no RASSF1A or BRAF mutation (V599E) was detected in any of the primary MM studied (n = 21), the latter was found in the U266 cell line. Taken together, these data indicate that alterations of RAS signalling are critical in MM pathogenesis. In our current studies of Chinese MM patients, these alterations involved frequent RASSF1A inactivation (60%) as a result of transcriptional silencing or expression of a non-functional variant transcript.
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PMID:Alterations of RAS signalling in Chinese multiple myeloma patients: absent BRAF and rare RAS mutations, but frequent inactivation of RASSF1A by transcriptional silencing or expression of a non-functional variant transcript. 1461 67

The identity of the cells responsible for the initiation and maintenance of multiple myeloma (MM) remains unclear largely because of the difficulty growing MM cells in vitro and in vivo. MM cell lines and clinical specimens are characterized by malignant plasma cells that express the cell surface antigen syndecan-1 (CD138); however, CD138 expression is limited to terminally differentiated plasma cells during B-cell development. Moreover, circulating B cells that are clonally related to MM plasma cells have been reported in some patients with MM. We found that human MM cell lines contained small (< 5%) subpopulations that lacked CD138 expression and had greater clonogenic potential in vitro than corresponding CD138+ plasma cells. CD138- cells from clinical MM samples were similarly clonogenic both in vitro and in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, whereas CD138+ cells were not. Furthermore, CD138- cells from both cell lines and clinical samples phenotypically resembled postgerminal center B cells, and their clonogenic growth was inhibited by the anti-CD20 monoclonal antibody rituximab. These data suggest that MM "stem cells" are CD138- B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells.
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PMID:Characterization of clonogenic multiple myeloma cells. 1463 Aug 3

The analysis of CD87 (urokinase-type plasminogen activator receptor - uPAR) expression has a potential role in the diagnostic or prognostic work-up of several hematological malignancies, particularly acute leukemia and multiple myeloma. The distribution of CD87 in acute myeloid leukemia (AML) varies according to the FAB subtype (highest expression in M5 and lowest in M0). Functionally, it is conceivable that the expression of CD87 could contribute to the invasive properties of the leukemic cells towards the skin and mucosal tissues as reflected by the clinical behavior of CD87 high cases. The lack of or weaker expression of CD87 on blast cells from ALL patients supports the concept that CD87 investigation might help in the distinction of AMLs from lymphoid malignancies. Among lymphoproliferative disorders, the expression of CD87 is exclusively found in pathological plasma cells. Since plasma cells also coexpress some adhesion molecules such as CD138 and CD56, this observation is consistent with the capacity of these cells to home in the bone compartment. High levels of soluble uPAR appear to represent an independent factor predicting worse prognosis and extramedullary involvement in multiple myeloma.
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PMID:CD87 (urokinase-type plasminogen activator receptor), function and pathology in hematological disorders: a review. 1467 31


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