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)

Recent studies have underscored the role of B-cell-activating factor (BAFF), a member of the tumor necrosis factor superfamily, in promoting the survival of malignant B cells, including human multiple myeloma. We here characterized the functional significance of BAFF in the interaction between multiple myeloma and bone marrow stromal cells (BMSC) and further defined the molecular mechanisms regulating these processes. BAFF is detected on BMSCs derived from multiple myeloma patients as evidenced by flow cytometry. BAFF secretion is 3- to 10-fold higher in BMSCs than in multiple myeloma cells, and tumor cell adhesion to BMSCs augments BAFF secretion by 2- to 5-fold, confirmed by both ELISA and immunoblotting. Adhesion of MM1S and MCCAR multiple myeloma cell lines to KM104 BMSC line transfected with a luciferase reporter vector carrying the BAFF gene promoter (BAFF-LUC) significantly enhanced luciferase activity, suggesting that nuclear factor-kappaB (NF-kappaB) activation induced by multiple myeloma adhesion to BMSCs mediates BAFF up-regulation. Moreover, BAFF (0-100 ng/mL) increases adhesion of multiple myeloma lines to BMSCs in a dose-dependent manner; conversely, transmembrane activator and calcium modulator and cyclophylin ligand interactor-Ig or B-cell maturation antigen/Fc blocked BAFF stimulation. Using adenoviruses expressing dominant-negative and constitutively expressed AKT as well as NF-kappaB inhibitors, we further showed that BAFF-induced multiple myeloma cell adhesion is primarily mediated via activation of AKT and NF-kappaB signaling. Importantly, BAFF similarly increased adhesion of CD138-expressing patient multiple myeloma cells to BMSCs. These studies establish a role for BAFF in localization and survival of multiple myeloma cells in the bone marrow microenvironment and strongly support novel therapeutics, targeting the interaction between BAFF and its receptors in human multiple myeloma.
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PMID:Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. 1681 41

Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.
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PMID:Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis. 1683 81

MHC class II is expressed in restricted lineages and is modulated in response to pathogens and inflammatory stimuli. This expression is controlled by MHC CIITA, which is transcribed from multiple promoters. Although factors required for induction of CIITA are well characterized, less is known about the mechanisms leading to repression of this gene. During plasma cell differentiation, B lymphocyte-induced maturation protein-1 (PRDM1/Blimp-1) represses promoter (p)III of CIITA, responsible for constitutive expression in B cells. pIV is inducible by IFN-gamma in epithelia, macrophages and B cells. An IFN regulatory factor-element (IRF-E) in CIITA-pIV, which is bound by IRF-1 and IRF-2, is necessary for this response. This site matches the PRDM1/Blimp-1 consensus binding site, and PRDM1/Blimp-1 is expressed in cell lineages in which this promoter is operative. We, therefore, investigated whether PRDM1 regulates CIITA-pIV and found that PRDM1 bound to CIITA-pIV in vivo and the IRF-E in vitro. PRDM1 repressed IFN-gamma-mediated induction of a CIITA-pIV luciferase reporter in a fashion dependent on an intact consensus sequence and competes with IRF-1/IRF-2 for binding to the IRF-E and promoter activation. In human myeloma cell lines that express IRFs, PRDM1 occupancy of CIITA-pIV was associated with resistance to IFN-gamma stimulation, while short interfering RNA knockdown of PRDM1 led to up-regulation of CIITA. Our data indicate that PRDM1 is a repressor of CIITA-pIV, identifying a target of particular relevance to macrophages and epithelia. These findings support a model in which PRDM1/Blimp-1 can modulate the cellular response to IFN-gamma by competing with IRF-1/IRF-2 dependent activation of target promoters.
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PMID:Repression of IFN-gamma induction of class II transactivator: a role for PRDM1/Blimp-1 in regulation of cytokine signaling. 1698 96

Neutralizing antiviral antibodies (Abs) can hinder systemic virotherapy. Here, we used activated T cells as carriers to deliver oncolytic measles viruses (MV) to multiple myeloma xenografts in the presence of anti-MV antibodies (Abs). Virus-infected T cells expressing measles H/F fusogenic envelope glycoproteins could efficiently transfer MV infection by heterofusion, even after exposure to virus-inactivating anti-MV antisera. Severe-combined immunodeficiency (SCID) mice bearing subcutaneous or disseminated human myeloma xenografts were given MV-luciferase (MV-Luc) or MV-Luc-infected T cells intravenously. Indium111 labeling indicated that 1-2% of the virus-infected T cells trafficked to tumors. Preinfected T cells fused with tumor cells in vivo and transferred MV-Luc to tumor xenografts where intratumoral viral spread was monitored non-invasively using bioluminescent imaging. In mice passively immunized with high titers of measles immune serum, intravenous virus and cell delivery were both inhibited. Decreasing the amount of measles immune serum given to mice permitted tumor infection by virus-infected T cells and cell-free virus. In conclusion, virus-loaded T cells may facilitate systemic measles virotherapy in the presence of antiviral Abs and they warrant further investigation as potential MV cell carriers.
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PMID:Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies. 1705 Dec 48

The establishment of clinically relevant human myeloma cell lines is central for our understanding of myeloma pathogenesis and development of novel therapies for the disease. Unfortunately, most available lines were generated from extramedullary sites, harbored multiple genetic abnormalities and categorized as non-hyperdiploid. In contrast, hyperdiploid myeloma cell lines, which represent more than 50% of patients, are rare. We established procedures for establishment of stroma-dependent myeloma lines by passaging primary myeloma cells, in severe combined immunodeficient-human (SCID-hu) or SCID-rab mice followed by maintenance in co-culture with stromal cells. We described the establishment and characterization of two hyperdiploid (LD and CF) and two non-hyperdiploid (JB and BN) cell lines. Using our animal models, we also established bortezomib-sensitive and -resistant BN lines. These cell lines were cellularly, phenotypically and molecularly characterized using flow cytometry immunophenotyping, DNA content, G-band and multicolor spectral karyotyping (SKY) and global gene expression profiling. All four cell lines were infected with lentiviral-expressing luciferase for detection of tumour cells at high sensitivity level and for monitoring myeloma growth in co-cultures and in vivo by live animal imaging. These myeloma cell lines and the procedures used for their establishment provide essential tools for studying myeloma biology and therapy.
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PMID:Establishment and exploitation of hyperdiploid and non-hyperdiploid human myeloma cell lines. 1802 78

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.
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PMID:A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin. 1787 8

Vascular endothelial growth factor (VEGF) is a survival and angiogenesis factor that is a target for therapy in a variety of cancers. In many hematological malignancies, VEGF production is increased leading to cell survival responses. Herein, we demonstrate that lysophosphatidic acid (LPA) induces mRNA expression of VEGF in the multiple myeloma cell line, U266, the Burkitt's lymphoma cell line, BJAB, and the chronic lymphocytic leukemia (CLL)-like cell line, I-83. This increase in mRNA levels of VEGF corresponded with increased luciferase activity of the VEGF promoter in BJAB and I-83 cells and increased protein levels in I-83 cells. Secretion of VEGF was also increased in these cells following LPA treatment. LPA treatment also caused the activation of both VEGFR1 and VEGFR2. The increase in VEGF expression by LPA is mediated by the activation of c-Jun N-terminal Kinase (JNK) and transcription factor NFkappaB since blocking JNK or NFkappaB activation inhibited LPA induced VEGF expression. Furthermore, we have demonstrated that LPA protects cells from apoptosis and blocking activation of both VEGFR1 and VEGFR2 using a VEGF receptor kinase inhibitor prevented LPA survival responses. Knocking down expression of VEGFR1 and inhibiting activation of NFkappaB and JNK also blocked LPA induced protection against apoptosis. Taken together, this indicates that LPA contributes to VEGF production in B cell malignancies leading to cell survival.
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PMID:Lysophosphatidic acid (LPA) induces the expression of VEGF leading to protection against apoptosis in B-cell derived malignancies. 1839 13

The transcription factor nuclear factor-kappa B (NF-kappaB) regulates the transcription of a number of genes involved in a variety of cellular responses, including cell survival, inflammation, and differentiation. NF-kappaB is activated by a variety of stimuli, proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. Aberrant NF-kappaB expression is considered to be one of the oncogenic factors of cancer and the constitutive activation of NF-kappaB is observed in several hematologic disorders [classic Hodgkin's lymphoma, diffuse large B cell lymphoma, and multiple myeloma (MM)], and the modulation of NF-kappaB activation is emerging as a promising novel anticancer therapeutic strategy.Therefore, we focused on the regulation of NF-kappaB activation in MM. When U266 cells were treated with 6-amino-4-quinazoline, an NF-kappaB activation inhibitor, we determined that it most effectively blocked the interleukin (IL)-6-induced activation of MAPK and JAK/STAT pathways among different signaling inhibitors. The results of the luciferase assay indicated that 6-amino-4-quinazoline inhibited NF-kappaB activation with diminished NF-kappaB protein bound to NF-kappaB DNA binding sites. In addition, 6-amino-4-quinazoline suppressed the production of IL-6, which affected MM cell proliferation. Furthermore, combined treatment with bortezomib and 6-amino-4-quinazoline effectively inhibited the IL-6 and soluble IL-6R-induced activation of STAT3 and extracellular signal-regulated kinase phosphorylation. Our data showed that the inhibition of NF-kappaB activation abrogated MM cell proliferation induced by the IL-6 pathway, and might represent a promising therapeutic strategy for the treatment of MM.
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PMID:Blockage of interleukin-6 signaling with 6-amino-4-quinazoline synergistically induces the inhibitory effect of bortezomib in human U266 cells. 1869 88

Multiple myeloma (MM) is an incurable B-cell neoplasia in which progressive skeletal lesions are a characteristic feature. Earlier we established an animal model for human MM in the immune-deficient RAG2(-/-)gammac(-/-) mouse, in which the growth of luciferase-transduced MM cells was visualized using noninvasive bioluminescence imaging (BLI). This model appeared well suited to study disease progression and response to therapy by identifying the location of various foci of MM tumor growth scattered throughout the skeleton and at subsequent time points the quantitative assessment of the tumor load by using BLI. We report here on the corresponding high-resolution X-ray micro-computed tomographic (micro-CT) analysis to study skeletal defects in the mice with full-blown MM. Several anatomical derangements were observed, including abnormalities in geometry and morphology, asymmetrical bone structures, decreased overall density in the remaining bone, loss of trabecular bone mass, destruction of the inner microarchitecture, as well as cortical perforations. Using the combination of BLI, micro-CT imaging, and immune-histopathological techniques, we found a high correlation between the micro-CT-identified lesions, exact tumor location, and infiltration leading to structural lesions and local bone deformation. This confirms that this animal model strongly resembles human MM and has the potential for studying the biology of MM growth and for preclinical testing of novel therapies for MM and for repair of MM-induced bone lesions.
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PMID:Correlation of high-resolution X-ray micro-computed tomography with bioluminescence imaging of multiple myeloma growth in a xenograft mouse model. 1981 49

Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, we developed the tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (for example, myeloma, leukemia and solid tumors) stably expressing luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells. A stroma-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-kappaB, HIF-1alpha, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anticancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stroma interactions.
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PMID:Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. 2022 16


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