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)

A humanized monoclonal antibody against HM1.24 antigen (AHM), which is highly expressed on multiple myeloma (MM) cells, induced antibody-dependent cellular cytotoxicity (ADCC) in vitro. In this study, we further characterized AHM and evaluated its potency for clinical application. AHM bound to HM1.24 antigen with a dissociation constant of 0.35 nM, and its epitope resided between Leu116 and Leu127 of the HM1.24 antigen. Single intravenous injection of AHM significantly inhibited tumor growth in both orthotopic and ectopic human MM xenograft models. AHM reduced serum M protein levels and prolonged survival of mice intravenously inoculated with KPMM2 and ARH-77 cells. The number of KPMM2 cells in bone marrow or tumor volume of subcutaneously inoculated RPMI 8226 cells was also inhibited by AHM. The antitumor activity of AHM against tumor cells in bone marrow was diminished when the mice were pretreated with anti-Fcgamma receptor III/II antibody, demonstrating that antitumor activity by AHM requires effector cell functions in vivo. Experiments involving in vitro ADCC assays indicated that NK cells and monocytes/macrophages serve as effector cells for AHM-induced ADCC in mouse and human. Thus, AHM will provide an additional treatment option for MM.
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PMID:Antitumor activity of humanized monoclonal antibody against HM1.24 antigen in human myeloma xenograft models. 1639 55

Cellular diversity, which is a hallmark of malignancy, can be generated by both genetic and nongenetic mechanisms. We describe here variability in the adhesive and migratory behavior of malignant plasma cell populations, including multiple myeloma-derived lines and primary patient samples. Examination of the plasma cell lines ARH-77, CAG, and AKR revealed two distinct subpopulations of cells, one displaying highly adhesive properties (type A) and the other consisting of poorly adhesive, floating cells (type F). In the ARH-77 cell line, type A cells attach better to fibronectin and to human bone fragments and form paxillin-rich focal adhesions, whereas type F cells are highly motile and exert integrin-dependent bone marrow homing capacity in nonobese diabetic/severe combined immunodeficient mice. Flow cytometry indicated that type A cells express significantly higher levels of CD45 and CD56 and lower levels of CD138 compared with type F cells. Interestingly, culturing of either type A or type F cells under nonselective conditions resulted in the development of mixed cell population similar to the parental ARH-77 cells. Analysis of bone marrow aspirates of multiple myeloma patients revealed that spicules within the aspirates are enriched with type A-like cells. Nonadherent cells within the aspirate fluids express a marker profile similar to type F cells. This study indicates that multiple myeloma patients contain heterogeneous populations of malignant plasma cells that display distinct properties. Diverse subpopulations of malignant plasma cells may play distinct roles in the different biological and clinical manifestations of plasma cell dyscrasias, including bone dissemination and selective adhesion to bone marrow compartments.
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PMID:The generation and regulation of functional diversity of malignant plasma cells. 1695 Nov 74

UV3 is a monoclonal antibody that recognizes human CD54 (intercellular adhesion molecule-1), and it was generated for the therapy of human multiple myeloma. In a severe combined immunodeficient (SCID) xenograft model of human multiple myeloma, UV3 significantly prolonged the survival of mice with either early or advanced stages of disease. However, the mechanism by which UV3 exerted its antitumor effect remained unknown. As reported previously UV3 could mediate antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity in vitro. F(ab)'2 fragments of UV3 had therapeutic efficacy in vivo, suggesting that effector functions were not critical. The purpose of this study was to further define the importance of the Fc portion of UV3 for its antitumor activity in vivo. To this end, we examined the effect of an "ultrapure" preparation of UV3 F(ab)'2 to treat SCID mice xenografted with either ARH-77 cells, a human multiple myeloma cell line, or Daudi cells, a human Burkitt's lymphoma cell line. In addition, we evaluated different doses of UV3 immunoglobulin G (IgG) in these mice to determine the minimum amount of IgG that would produce a therapeutic effect. Data obtained from this study suggest that (1) the Fc portion of UV3 is critical for its antitumor activity in vivo, (2) low levels of UV3 IgG in a preparation of F(ab)'2 fragments account for all of its in vivo activity in multiple myeloma and most of its activity in lymphoma, and (3) UV3 IgG significantly prolongs the survival of SCID/ARH-77 mice as well as SCID/Daudi mice.
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PMID:The Fc portion of UV3, an anti-CD54 monoclonal antibody, is critical for its antitumor activity in SCID mice with human multiple myeloma or lymphoma cell lines. 1697 5

The innate antiviral responses of tumor cells are often impaired but may still be sufficient to impede the intratumoral spread of an oncolytic virus. Here, we establish that the oncolytic measles virus (MV-eGFP) induces interferon (IFN) production in human myeloma and ovarian cancer cells. In addition, MV gene expression and virus progeny production were inhibited by IFN treatment of these tumor cells. The P gene of wild-type measles virus encodes P/V/C proteins known to antagonize IFN induction and/or response. We therefore engineered MV-eGFP for IFN evasion and more efficient intratumoral spread by arming it with the P gene from wild-type IC-B strain MV, thus generating MV-eGFP-Pwt. The chimeric virus exhibited reduced IFN sensitivity and diminished capacity to induce IFN in BJAB lymphoma, ARH-77 myeloma cells, and activated peripheral blood mononuclear cells. Interestingly, unlike the wild-type MV, MV-eGFP-Pwt was unable to shut down IFN induction completely. In immunocompromised mice bearing human myeloma xenografts, intravenously administered MV-eGFP-Pwt showed significantly enhanced oncolytic potency compared to MV-eGFP. These results indicate that oncolytic viruses are subject to control by the innate immune defenses of human tumor cells and may therefore be more effective if their natural ability to combat innate immunity is maintained.
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PMID:Engineering oncolytic measles virus to circumvent the intracellular innate immune response. 1724 55

Adhesion of myeloma cells to bone marrow stromal cells is now considered to play a critical role in chemoresistance. However, little is known about the molecular mechanism governing cell adhesion-mediated drug resistance (CAM-DR) of myeloma cells. In this study, we focused our interests on the implication of the Wnt signal in CAM-DR. We first screened the expression of Wnt family in myeloma cell lines and found that Wnt3 was overexpressed in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human bone marrow stromal cells, and accumulation of beta-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPMI8226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human bone marrow stromal. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against doxorubicin. This CAM-DR was significantly reduced by anti-integrin beta(1) antibody, anti-integrin alpha(6) antibody and a Wnt-receptor competitor, secreted Frizzled-related protein-1, and Rho kinase inhibitor Y27632, but not by the specific inhibitor of canonical signaling (Dickkopf-1), indicating that Wnt-mediated CAM-DR that is dependent on integrin alpha(6)/beta(1) (VLA-6)-mediated attachment to stromal cells is induced by the Wnt/RhoA/Rho kinase pathway signal. This CAM-DR was also significantly reduced by Wnt3 small interfering RNA transfer to KMS-5. These results indicate that Wnt3 contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells in an autocrine manner. Thus, the Wnt3 signaling pathway could be a promising molecular target to overcome CAM-DR of myeloma cells.
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PMID:Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism. 1757 6

Resistance towards the proteasome inhibitor bortezomib is poorly understood. We adapted the HL-60, ARH-77 and AMO-1 cell lines (myeloid leukemia, plasmocytoid lymphoma, myeloma) to bortezomib exceeding therapeutic plasma levels, and compared characteristics of the ubiquitin-proteasome system, alternative proteases and the unfolded protein response (UPR) between adapted cells and parental lines. Adapted cells showed increased transcription rates, activities and polypeptide levels of the bortezomib-sensitive beta5, but also of the beta2 proteasome subunit and consistently retained elevated levels of active beta1/beta5-type proteasome subunits in the presence of therapeutic levels of bortezomib. Bortezomib-adapted HL-60 cells showed increased expression and proteasome association of the 11S proteasome activator, and did not accumulate poly-ubiquitinated protein, activate the UPR or UPR-mediated apoptosis in response to bortezomib. The rate of protein biosynthesis was reduced, and the transcription of chaperone genes downmodulated. We did not observe major changes in the activities of TPPII, cathepsins or deubiquitinating proteases. We conclude that different types of bortezomib-adapted cell lines, including myeloma, show similar patterns of changes in the proteasomal machinery which result in residual proteasome activity in the presence of bortezomib and a quantitative balance between protein biosynthesis and destruction.
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PMID:Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. 1922 32

Genetic and epigenetic changes in multiple myeloma (MM) correlate with the stage of the disease. Therefore, we investigated how cytostatics and gamma radiation influence MM-associated histone modifications. ChIP-PCR and ChIP-on-chip technologies were used to quantify H3K9 acetylation and H3K9 dimethylation at select loci in MM patients, lymphoblastoid ARH-77, and myeloma MOLP-8 cells. Genome-wide analysis revealed that the cytostatic, melphalan, increased H3K9 acetylation at multiple gene promoters in ARH-77 cells. Melphalan and gamma radiation also influenced histone modification of prognostically important c-myc and CCND1 genes in ARH-77 and MOLP-8 cells. Moreover, H3K9 acetylation at c-myc and CCND1 promoters was increased in individual MM patients after melphalan treatment. Western blotting revealed that these effects were accompanied by changes in c-MYC and cyclin D1 protein levels. Taken together, we showed that cytostatics significantly alter histone modification of tumor-related genes which is indispensable for understanding cancer therapies.
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PMID:Epigenetics of multiple myeloma after treatment with cytostatics and gamma radiation. 1936 68

Chromosomal rearrangements and copy number variation are frequently observed in cancer cells, including multiple myeloma (MM). Karyotypic abnormalities seen in MM cells correlate with the disease stage and drug responses. Here, we investigate the nuclear arrangement of the 1q21 region; amplification of this region is an important diagnostic and prognostic marker of MM. We examined the lymphoblastoid cell line CD138- ARH-77, multiple myeloma CD138+ MOLP-8 cells, and the CD138+ bone marrow fraction of patients diagnosed with MM. In this experimental system, we observed that gamma-radiation and selected cytostatic drugs such as melphalan and dexamethasone did not significantly alter the nuclear radial arrangement of the 1q21 region and other relevant regions of chromosome 1. Similarly, conserved nuclear radial positioning after cytostatic treatment was observed for the c-myc, TP53, CCND1, and IgH loci. When analyzed Mcl-1, a protein encoded by a gene mapped to the 1q21 region, we found that the variant Mcl1S is highly expressed in multiple myeloma MOLP-8 cells, but not in peripheral blood lymphocytes of healthy donors or lymphoblastoid ARH-77 cells; this is in contrast to the expression pattern of the Mcl-1L variant. On the basis of these observations we suggest that the 1q21 region is an important diagnostic marker of MM, particularly the gene encoding the Mcl-1S variant, which can be easily detected by western analysis.
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PMID:Nuclear topography of the 1q21 genomic region and Mcl-1 protein levels associated with pathophysiology of multiple myeloma. 1958 Mar 42

The genetic profiling of B-cell malignancies is rapidly expanding, providing important information on the tumorigenic potential, response to treatment, and clinical outcome of these diseases. However, the relative contributions of inherent gene expression versus microenvironmental effects are poorly understood. The regulation of gene expression programs by means of adhesive interactions was studied here in ARH-77 human malignant B-cell variants, derived from the same cell line by selective adhesion to a fibronectin matrix. The populations included cells that adhere to fibronectin and are highly tumorigenic (designated "type A" cells) and cells that fail to adhere to fibronectin and fail to develop tumors in vivo ("type F" cells). To identify genes directly affected by cell adhesion to fibronectin, type A cells deprived of an adhesive substrate (designated "AF cells") were also examined. Bioinformatic analyses revealed a remarkable correlation between cell adhesion and both B-cell differentiation state and the expression of multiple myeloma (MM)-associated genes. The highly adherent type A cells expressed higher levels of NFkappaB-regulated genes, many of them associated with MM. Moreover, we found that the transcription of several MM-related proto-oncogenes is stimulated by adhesion to fibronectin. In contrast, type F cells, which display poor adhesive and tumorigenic properties, expressed genes associated with higher levels of B-cell differentiation. Our findings indicate that B-cell differentiation, as manifested by gene expression profiles, is attenuated by cell adhesion to fibronectin, leading to upregulation of specific genes known to be associated with the pathogenesis of MM.
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PMID:Adhesive interactions regulate transcriptional diversity in malignant B cells. 2037 71

Many monoclonal antibodies (mAbs) have been extensively used in the clinic, such as rituximab to treat lymphoma. However, resistance and non-responsiveness to mAb treatment have been challenging for this line of therapy. Complement is one of the main mediators of antibody-based cancer therapy via the complement-dependent cytolysis (CDC) effect. CD59 plays a critical role in resistance to mAbs through the CDC effect. In this paper, we attempted to investigate whether the novel CD59 inhibitor, recombinant ILYd4, was effective in enhancing the rituximab-mediated CDC effect on rituximab-sensitive RL-7 lymphoma cells and rituximab-induced resistant RR51.2 cells. Meanwhile, the CDC effects, which were mediated by rituximab and anti-CD24 mAb, on the refractory multiple myeloma (MM) cell line ARH-77 and the solid tumor osteosarcoma cell line Saos-2, were respectively investigated. We found that rILYd4 rendered the refractory cells sensitive to the mAb-mediated CDC effect and that rILYd4 exhibited a synergistic effect with the mAb that resulted in tumor cells lysis. This effect on tumor cell lysis was apparent on both hematological tumors and solid tumors. Therefore, rILYd4 may serve as an adjuvant for mAb mediated-tumor immunotherapy.
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PMID:Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells. 2125 60


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