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)

Our group recently reported that multiple myeloma (MM) cells preferentially adhere to bone marrow (BM) endothelial cells and selectively home to the BM, suggesting the involvement of specific adhesive interactions in this process. The highly regulated expression of CD44 variant isoforms (CD44v) on the MM cells makes them good candidate adhesion molecules involved in this homing. We addressed this in the 5T experimental mouse model of myeloma. Fluorescence-activated cell sorting analysis demonstrated expression of CD44v6, CD44v7, and CD44v10 on the in vivo growing 5T2MM and 5T33MM myeloma lines. Antibody blocking experiments revealed the involvement of CD44v10 in the adhesion of 5T2MM and 5T33MM cells to BM endothelial cells. Coinjection of anti-CD44v10 antibodies with the myeloma cells into syngeneic mice demonstrated a selective blocking of their BM homing which resulted in a decreased BM tumor load and serum paraprotein at the end stage of the disease. The highly restricted expression of CD44v10 on MM cells, the blocking of MM adhesion to BM endothelial cells and of homing to BM by anti-CD44v10, and the decreased BM tumor load suggest that myeloma cells home to the BM via interactions mediated by this specific region of the adhesion molecule CD44.
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PMID:A unique pathway in the homing of murine multiple myeloma cells: CD44v10 mediates binding to bone marrow endothelium. 1130 59

To evaluate the role of CD44 variant isoforms (CD44v) in plasma cell dyscrasias, CD44v expression was analysed in bone marrow (BM) biopsies of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) patients, in biopsies of soft tissue infiltration by MM and in extramedullary plasmacytoma samples. Expression of CD44 isoforms containing the 3v, 4v, 6v or 10v domain was observed in 15, 7, 13 and 5% of 87 samples from 49 consecutive MM cases, but could not be detected in ten normal persons or 11 MGUS patients. In contrast, CD44v9 revealed a broader pattern of expression and was observed in plasma cells in three out of ten normal persons and in three out of 11 MGUS cases. In MM, CD44v9 was detected in 32 out of 87 samples (37%) of BM infiltrates and was associated with an advanced Durie and Salmon stage (P<0.03), a progressive disease (P<0.01) and an IgA subtype (P<0.01). Furthermore, CD44v9 expression was observed in three out of five cases of MM soft tissue infiltrates, was often upregulated during disease progression, was significantly correlated with a shorter overall survival (P<0.03) and emerged as an independent prognostic factor in multivariate analysis (stage: relative risk 1.36, P<0.02; CD44v9 expression: relative risk 1.45, P<0.04). These results substantiate the clinical relevance of CD44v domains in plasma cell disorders and establish CD44v9 as a new independent prognostic parameter in MM.
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PMID:CD44 isoforms are differentially regulated in plasma cell dyscrasias and CD44v9 represents a new independent prognostic parameter in multiple myeloma. 1168 76

The 26S proteasome regulates protein turnover in eukaryotic cells. This is relevant in human cancer because the cell cycle, tumor growth, and survival are governed by a large repertoire of intracellular proteins that are regulated by the ubiquitin-mediated proteasome degradative pathway. In the development of new antitumor agents whose mechanisms are distinct from currently available therapies, we have discovered a potent, selective inhibitor of the proteasome: PS-341, a dipeptide boronic acid. Compared with normal cells, cancer cells--and specifically myeloma--treated with PS-341 are differentially sensitive to proteasome inhibition and apoptosis. A unique feature of PS-341 involves the inhibition of nuclear factor (NF)-kappaB activation through stabilization of the inhibitor protein IkappaB. Myeloma cells depend on NF-kappaB-mediated transcription of cytokine growth factor interleukin-6, angiogenesis through vascular endothelial growth factor, and the cell adhesion molecule VCAM-1 for adherence of the plasma cells to the stromal tissue in bone marrow. At low nanomolar concentrations, PS-341 is highly effective in abrogating the transcription of these genes, which are under the direct regulation of NF-kappaB. Moreover, PS-341 appears to synergize with dexamethasone in myeloma cell culture, which may prove to be of additional benefit clinically. The safety profile in phase I trials of PS-341 in patients with cancer appears encouraging. Because proteasome inhibition with PS-341 results in potent antitumor activity in vitro, PS-341 may offer a promising new approach to treating otherwise fatal malignancy.
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PMID:Proteasome inhibition in cancer: development of PS-341. 1174 Aug 19

Expression of CD44v9-containing isoforms (CD44v9) on myeloma plasma cells correlates with unfavorable prognosis, suggesting that CD44 variant molecules are involved in the disease process. In this study, the presence of CD44v on B cell lines from different stages of development was analyzed by flow cytometry and a role in adhesion to stromal cells from different tissues was evaluated in in vitro binding assays. CD44v3, v6 and v9 isoforms were exclusively expressed on plasma cell lines and CD44v9 expression correlated with IL-6-dependent plasma cell growth. Binding studies using CD44 isoform- specific reagents showed that CD44v6 and CD44v9 were involved in binding to bone marrow stromal cells, but not to in vitro synthesized ECM or hyaluronic acid. CD44v9-mediated plasma cell binding resulted in a significant induction of IL-6 secretion by bone marrow stromal cells. Large differences in quantitative plasma cell binding to stromal cells from different tissues were observed. These, however, could not be related to a differential use of CD44v in these binding processes. The role of CD44v9 in adhesion induced IL-6 secretion and its preferential expression on IL-6-dependent plasma cell lines may explain the previously observed correlation between CD44v9 expression and adverse prognosis in multiple myeloma.
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PMID:CD44 variant isoforms are involved in plasma cell adhesion to bone marrow stromal cells. 1184 Feb 73

A 70-year-old woman was admitted for anemia, elevated serum total protein and a right axillary mass. Laboratory data showed monoclonal x IgM with a decrease in serum IgG and IgA levels. An occipital punched-out lesion was detected on a cranial X-ray. A tumor lesion was detected on chest X-ray and computed tomography. Biopsy specimen revealed plasmacytoma with cytoplasmic IgM. Bone marrow aspiration revealed an elevated plasma cell count. An immunophenotype analysis of the plasma cells showed positivity of cytoplasmic IgM, x, CD5, CD38, CD11a (LFA-1), CD44 (HCAM), CD49d (VLA-4) and CD54 (ICAM-1). From the above results, we diagnosed the patient as having IgM myeloma associated with plasmacytoma. Melphalan and prednisolone therapy were prescribed, their effect on the myeloma was short term, so we changed the chemotherapy to VAD (vincristine, adriamycin and dexamethasone), but this treatment had little effect. The patient developed bacterial pneumonia and died. IgM myeloma is a rare disease and reports of immunophenotype analysis are also rare. There is no case report of plasmacytoma associated with IgM myeloma.
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PMID:[IgM type multiple myeloma expressing various surface adhesion molecules and demonstrating an aggressive clinical course]. 1457 17

We generated fully human mAbs (HmAbs) to carcinoembryonic antigen (CEA) using the KM mouse, which carries a human chromosome 14 fragment containing the entire Ig H chain loci and human kappa L chain segments in the mouse genome. Forty-six hybridoma clones producing HmAbs to CEA were thus obtained by fusing the P3-U1 mouse myeloma cells with splenocytes of the KM mice immunized with CEA. Among them, 22 clones produced HmAbs that reacted with CEA but not with 3 other CEA-related cell adhesion molecule (CEACAM) family members, CEACAM1, CEACAM6 and CEACAM8. In 12 HmAbs examined, 8 were IgG4, 2 were IgG3, 1 was IgG2, and the other was IgG1. The affinity constants for CEA of these HmAbs were comparable to those of the previously prepared mouse anti-CEA mAbs (MmAbs). BIAcore analyses revealed that 1 and 2 of the 22 HmAbs react with 2 epitopes defined by MmAbs on the domain N and the domain A1 or B1 of CEA, respectively. In the presence of human complement in vitro, 2 HmAbs tested showed substantial cytotoxicity, namely, 50-65%, against CEA-expressing tumor cells. With human lymphokine-activated killer cells in vitro, 3 HmAbs tested exhibited 40-65% Ab-dependent cell-mediated cytotoxicity against the tumor cells. Moreover, one of the HmAbs induced a significant inhibition of tumor growth when administered to mice xenografted with the CEA-expressing cells. Considering their lack of immunogenicity to humans, these CEA-specific HmAbs may be useful for immunotherapeutic approaches as well as for immunodiagnosis.
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PMID:Generation, immunologic characterization and antitumor effects of human monoclonal antibodies for carcinoembryonic antigen. 1469 21

Multiple myeloma (MM) is a progressive B-lineage neoplasia characterized by the accumulation of slow proliferative malignant plasma cells in the bone marrow compartment where the microenvironment seems to be favorable for their growth and survival. Heparan sulfate proteoglycans such as syndecan-1 and CD44 are thought to play a central role in the survival signals provided by these bone marrow survival niches, which require complex interactions between myeloma cells, extracellular matrix, stromal cells and soluble factors. In this report, we demonstrate that interleukin-6 (IL-6), the main survival and growth factor for myeloma cells, strongly increases CD44 gene expression. In addition, we show that IL-6 modulates CD44 RNA alternative splicing and induces the overexpression of all CD44 variant exons. Finally, we show that IL-6-induced CD44 cell surface molecules have a functional polarized membrane distribution. As IL-6 secretion induced from bone marrow stromal cells by myeloma cells is partly mediated through direct cell-to-cell interaction involving CD44 adhesion molecules, our findings suggest that a CD44/IL-6 amplification loop plays a crucial role in myeloma cell survival.
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PMID:IL-6 regulates CD44 cell surface expression on human myeloma cells. 1501 27

Mucosal addressin cell adhesion molecule (MAdCAM-1) is a key player in mediating the infiltration of leucocytes into chronically inflamed tissues. Five anti-MAdCAM-1 monoclonal antibodies (mAb), designated 17F5, 201F7, 314G8, 377D10 and 355G8, were generated by fusion of P3 x 63Ag8.653 myeloma cells with spleen cells from BALB/c mice immunized with recombinant human MAdCAM-1-Fc. The latter four mAb recognize the ligand-binding first Ig domain, and block T -cell adhesion to MAdCAM-1. The non-blocking mAb 17F5 recognizes the mucin domain. Extensive analysis of a large panel of paraffin-embedded human tissues revealed that the 314G8 mAb detected MAdCAM-1 on venules in the spleen and small intestine. MAdCAM-1 was strongly expressed in the synovium of osteoarthritis patients, predominantly on the endothelial lining of blood vessels, but also within the vessel lumen. An ELISA, based on mAb 377D10 and 355G8, was developed to determine whether soluble MAdCAM-1 was present in body fluids, and to measure the levels present. The assay detected soluble MAdCAM-1 in the serum and urine of healthy donors, at levels similar to those of soluble forms of the related CAM, ICAM-1 and VCAM-1. The anti-MAdCAM-1 antibodies and assay developed here may be useful therapeutically in the treatment of inflammation in humans. Similarly, they may be useful diagnostically to monitor the presence and levels of MAdCAM-1.
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PMID:Bioassay detects soluble MAdCAM-1 in body fluids. 1528 50

We evaluated the serum/plasma levels of cytokines [interleukin (IL)-6, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta2] and markers of coagulation, fibrinolysis, endothelial and platelet activation during the first 4 wk of treatment with the thalidomide analogue Actimid (CC-4047) in 15 patients with relapsed/refractory myeloma. There was evidence of activation of endothelium (soluble vascular cell adhesion molecule, sVCAM), coagulation (prothrombin fragment 1 + 2, PF1 + 2) and fibrinolysis (D-dimers) but no evidence of platelet activation or endothelial cell damage in myeloma patients. These parameters were not affected by the use of CC-4047. Three of four patients with baseline D-dimers levels >500 microg/L subsequently developed deep vein thrombosis (DVT). The hypothesis that D-dimer level >500 microg/L may predict for those patients most at risk of thromboembolism with multiple myeloma undergoing treatment is worthy of further study.
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PMID:Markers of endothelial and haemostatic function in the treatment of relapsed myeloma with the immunomodulatory agent Actimid (CC-4047) and their relationship with venous thrombosis. 1577 40

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


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