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)

The novel multiple myeloma (MM) cell line MOLP-8 carrying the t(11;14) (q13;q32) was established from the peripheral blood of a 52-year-old Japanese male patient with Bence-Jones delta/lambda type MM (stage IIIA with hyperammonemia). The growth of MOLP-8 cells is constitutively independent of exogenous growth factors or feeder cells. MOLP-8 cells grow mainly as free floating single cells and slightly adherent on the bottom of the plastic culture flask. Wright-Giemsa-stained MOLP-8 cells show the typical plasma cell morphology with abundant cytoplasm, heterogeneous cell size and one to three nuclei. The immunoprofile of MOLP-8 corresponds to that seen typically in primary MM cells: positive for cytoplasmic immunoglobulin (Ig) delta/lambda chains, CD10, CD29, CD38, CD40, CD44, CD49b, CD49d, CD54, CD56, CD58, CD71, CD138 and PCA-1; the cells were negative for surface Igs and various other B-cell, T-cell and myelomonocyte-associated immunomarkers. CD28 became positive after co-culture of MOLP-8 cells with bone marrow adherent stromal (BST) feeder cells for a week. About 30% of MOLP-8 cells adhered strongly to the BST cells, but the cellular adhesion was clearly inhibited by addition of either anti-CD29 or anti-CD106 monoclonal antibody, suggesting a specific cellular adhesion through alpha4beta1-integrin-VCAM-1 interaction. The novel MOLP-8 cell line together with the present myeloma cell lines will present useful model systems in the investigation of the biology of MM.
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PMID:Induction of CD28 on the new myeloma cell line MOLP-8 with t(11;14)(q13;q32) expressing delta/lambda type immunoglobulin. 1520 85

Front-rear asymmetry in motile cells is crucial for efficient directional movement. The uropod in migrating lymphocytes is a posterior protrusion in which several proteins, including CD44 and ezrin/radixin/moesin (ERM), are concentrated. In EL4.G8 T-lymphoma cells, Thr567 phosphorylation in the COOH-terminal domain of ezrin regulates the selective localization of ezrin in the uropod. Overexpression of the phosphorylation-mimetic T567D ezrin enhances uropod size and cell migration. T567D ezrin also induces construction of the CD44-associated polar cap, which covers the posterior cytoplasm in staurosporine-treated, uropod-disrupted EL4.G8 cells or in naturally unpolarized X63.653 myeloma cells in an actin cytoskeleton-dependent manner. Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor Y-27632 disrupts the uropod but not the polar cap, indicating that Rho-ROCK signaling is required for posterior protrusion but not for ERM phosphorylation. Phosphorylated ezrin associates with Dbl through its NH2-terminal domain and causes Rho activation. Moreover, constitutively active Q63L RhoA is selectively localized in the rear part of the cells. Thus, phosphorylated ERM has a potential function in establishing plasma membrane "posteriority" in the induction of the uropod in T lymphocytes.
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PMID:Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. 1550 14

Nuclear morphological alterations associated with glucocorticoid resistance in human myeloma were evaluated by image cytometry in three human myeloma RPMI 8226 cell sub-lines. Resistance was induced by drug selection using prednisone (8226p), methylprednisolone (8226m) and dexamethasone (8226d), respectively. All these three cell sub lines displayed significant glucocorticoid-resistance without cross-resistance to doxorubicin. Nuclear geometry and texture were analyzed on G0/G1-selected cell nuclei and data compared with cell growth characteristics and membrane expression of CD23, CD38, CD44 and CD58 antigens. When compared to the parental RPMI 8226 cell line, glucocorticoid-resistant cells display a progressive chromatin condensation with heterogeneously distributed large chromatin clumps, a phenomenon not observed in the multidrug-resistant CEM-VLB cells. These alterations were correlated to the resistance index against glucocorticoids and to the expressions of CD38, and of CD44 variant forms CD44v5 and CD44v7-8 antigens. These data suggest that glucocorticoid resistance in RPMI 8226 cells could be associated with sub-visual specific higher-order chromatin organization changes. Furthermore, these alterations are correlated to the expression of membrane markers associated with tumors aggressiveness.
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PMID:Nuclear chromatin patterns in 3 glucocorticoid-resistant RPMI 8226 human myeloma cell sub-lines: correlations with cell growth and immunological phenotype. 1621 Sep 12

Hematopoietic stem cell transplantation (HSCT) has become the standard of care for the treatment of many hematologic malignancies, chemotherapy sensitive relapsed acute leukemias or lymphomas, multiple myeloma; and for some non-malignant diseases such as aplastic anemia and immunodeficient states. The hematopoietic stem cell (HSC) resides in the bone marrow (BM). A number of chemokines and cytokines have been shown in vivo and in clinical trials to enhance trafficking of HSC into the peripheral blood. This process, termed stem cell mobilization, results in the collection of HSC via apheresis for both autologous and allogeneic transplantation. Enhanced understanding of HSC biology, processes involved in HSC microenvironmental interactions and the critical ligands, receptors and cellular proteases involved in HSC homing and mobilization, with an emphasis on G-CSF induced HSC mobilization, form the basis of this review. We will describe the key features and dynamic processes involved in HSC mobilization and focus on the key ligand-receptor pairs including CXCR4/SDF1, VLA4/VCAM1, CD62L/PSGL, CD44/HA, and Kit/KL. In addition we will describe food and drug administration (FDA) approved and agents currently in clinical development for enhancing HSC mobilization and transplantation outcomes.
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PMID:Cytokines and hematopoietic stem cell mobilization. 1688 4

The aim of this study was to investigate the growth, immunophenotype and interleukin-6 (IL-6) level of bone marrow stromal cells (BMSC) in patients with acute leukemia (AL) and multiple myeloma (MM). BMSC was cultured by wall-adhesion method and the growth of BMSC was observed. The immunophenotype and cell cycle of BMSC were detected by flow cytometry. The level of interleukin 6 (IL-6) in BMSC culture system was detected by ELISA. The results showed that the primary (17.3 +/- 7.8 days) and continuous (10.3 +/- 3.5 days) growth cycle of BMSC in patients with AL were significantly shorter than those in patients with MM (26.5 +/- 6.3 and 16.5 +/- 4.1 days respectively), and shorter than those in normal controls (25.8 +/- 6.3 and 17.5 +/- 2.4 days) respectively. Similarly, S + G2% (17.4 +/- 3.6%) of BMSC in patients with AL was significantly higher than those in patients with MM (8.5 +/- 2.2%) and in normal controls (8.9 +/- 2.3%). All of the three groups showed positive antigen expressions with CD29 and CD44 were 100%, while CD138, CD34, CD54, CD56 positive were not expressed and CD106 was partially expressed positive. The supernatant IL-6 level of BMSC system in MM patients (1288.5 +/- 736.7 pg/ml) was significantly higher than those in AL patients (859.3 +/- 203.1 pg/ml) and normal controls (850.9 +/- 129.5 pg/ml). It is concluded that the growth, S + G2% of cell cycle and IL-6 level of BMSC in patients with MM, AL and normal control are significantly different, whereas the antigen expressions are similar.
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PMID:[Growth, immunophenotype and interleukin-6 level of bone marrow stromal cells in patients with multiple myeloma and acute leukemia]. 1692 3

AMD3100, a competitive antagonist of CXCR-4, disrupts the binding of its ligand, stromal cell-derived factor-1 (SDF-1), and facilitates stem cell mobilisation in patients with haematological malignancies. This study investigated the differential kinetics of CXCR-4 and adhesion molecule expression and their impact on stem cell yield during mobilisation with granulocyte-colony stimulating factor (G-CSF) (days 1-4) followed by AMD3100 in 10 patients with multiple myeloma. A four-colour flow cytometry-based determination of CXCR-4, VLA-4, L-selectin, PECAM, LFA-1 and CD44 expression on CD34+ cells and measurement of SDF-1 concentration were performed at different time points. After G-CSF alone, CXCR-4 expression on patients' blood and marrow CD34+ cells was significantly lower than in the healthy controls (p < 0.001), but allowed no prediction of stem cell yield. Except in the single poorly mobilising patient, AMD3100 led to a further significant decrease of CXCR4 (p = 0.001), which inversely correlated with the CD34+ counts in the blood (p = 0.005). SDF-1 level in patients' marrow was positively correlated with CXCR-4 expression on CD34+ cells (p = 0.011). It is interesting to note that the expression of adhesion molecules remained unaffected by AMD3100 administration. Further studies will define the possible prognostic role of AMD3100 mediated changes in CXCR-4 expression for the prediction of stem cell yield attainable with this new mobilisation regimen.
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PMID:Kinetics of CXCR-4 and adhesion molecule expression during autologous stem cell mobilisation with G-CSF plus AMD3100 in patients with multiple myeloma. 1743 11

Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM. In the present report, we describe isolation of a CD44-expressing population from a Dex-sensitive MM cell line, RPMI8226, in which the CD44-high population had a significantly higher potential to resist Dex than did the CD44-low population. Furthermore, we demonstrate that CD44 engagement by an anti-CD44 monoclonal antibody (mAb) or HA protects MM cells from Dex-induced growth inhibition. The activity of HA was partially inhibited by blocking its binding to CD44, indicating that CD44 mediates HA activity promoting MM cell survival. CD44 engagement by an anti-CD44 mAb led to phosphorylation and degradation of IkappaB-alpha, thus preventing its Dex-induced up-regulation. Our data suggest that CD44 is not only an important mediator for the survival activity of HA, but it may also contribute to MM cell resistance to Dex.
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PMID:CD44 and hyaluronan engagement promotes dexamethasone resistance in human myeloma cells. 1808 9

To investigate the effects of matrine on apoptosis and expression of adhesion molecules in human multiple myeloma cell line RPMI8226 cells, RPMI8226 cells were incubated with indicated concentrations of matrine. The growth of RPMI8226 cells was observed by CCK-8 colorimetric assay and apoptosis was detected by flow cytometry using Annexin V-FITC/PI staining. The cell cycles were analyzed by PI staining. Flow cytometry using Annexin V-FITC/PI staining was used to detect the expression of cell adhesion molecules, including CD44, CD44v6, CD54 and CD106. The results showed that RPMI8226 cell viability in presence of matrine decreased markedly in a dose- and time-dependent manners. The apoptosis could be induced by matrine and its level increased following the augmentation of the drug concentration. After treated by matrine for 48 hours, a concentration-dependent increase of cells in G(0)/G(1) phase and a decrease in S phase could be detected, but no obvious change of cell count was found in G(2)/M phase. Treatment of RPMI8226 cells with matrine for 48 hours resulted in decrease of expression levels of CD44 and CD54, while expressions of CD44v6 and CD106 had no significant change. It is concluded that matrine induces in vitro apoptosis, suppresses proliferation in multiple myeloma cells and depresses expression of some adhesion molecules.
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PMID:[Effects of matrine on the apoptosis and expression of adhesion molecule in multiple myeloma RMPI8226 cells]. 1831 8

Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we performed functional screening using short hairpin RNA (shRNA) to define the molecule(s) responsible for CAM-DR of MM. Using four bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226 and U266) and primary myeloma cells, we identified CD29 (beta1-integrin), CD44, CD49d (alpha4-integrin, a subunit of VLA-4), CD54 (intercellular adhesion molecule-1 (ICAM-1)), CD138 (syndecan-1) and CD184 (CXC chemokine receptor-4 (CXCR4)) as major adhesion molecules expressed on MM. shRNA-mediated knockdown of CD49d but not CD44, CD54, CD138 and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib, vincristine, doxorubicin and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was relatively resistant to CAM-DR because of its ability to specifically downregulate CD49d expression. This property was unique to bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.
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PMID:Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. 1885 9

Several components of the Wnt signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances beta-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling.
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PMID:BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells. 1973 61


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