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)

Myeloma cells specifically localize in the bone marrow and rarely circulate in blood. To study whether this immobilization could be partially explained by the presence of constitutively activated integrins, particularly alpha4beta1, we used the activation reporter HUTS-21 anti-beta1 mAb. These analyses showed that beta1 integrins on myeloma cells were moderately active and could be upregulated similarly to integrins on lymphoma or leukemia cells. Myeloma cells were also tested for their ability to attach to RGD-containing fibronectin fragments, a property of activated (but not resting) alpha4beta1. Two cell lines adhered to these fragments and this was inhibited by anti-alpha5 but not by anti-alpha4 mAbs. These results show that myeloma cells bear low/moderately active alpha4beta1 and support the notion that multiple interactions contribute to their localization in the bone marrow.
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PMID:Analysis of the activation state of alpha4beta1 integrin in human B cell lines derived from myeloma, leukemia or lymphoma. 942 40

Previous studies have shown that triggering multiple myeloma (MM) cells via CD40 induces IL-6-mediated autocrine growth as well as increased expression of cell surface adhesion molecules including CD11a, CD11b, CD11c, and CD18. In this study, we generated the 5E2 mAb which targets an antigen that is induced upon CD40 ligand (CD40L) activation of MM cells. Immunofluorescence, immunoprecipitation, and protein sequencing studies identified the target antigen of 5E2 mAb as the 86-kD subunit of the Ku autoantigen. We demonstrate that increased cell surface expression of Ku on CD40L-treated cells is due to migration of Ku from the cytoplasm to the cell surface membrane. Moreover, cell surface Ku on CD40L-treated MM cells mediates homotypic adhesion of tumor cells, as well as heterotypic adhesion of tumor cells to bone marrow stromal cells and to human fibronectin; and 5E2 mAb abrogates IL-6 secretion triggered by tumor cell adherence to bone marrow stromal cells. These data suggest that CD40L treatment induces a shift of Ku from the cytoplasm to the cell surface, and are the first to show that Ku functions as an adhesion molecule. They further suggest that cell surface Ku may play a role in both autocrine and paracrine IL-6-mediated MM cell growth and survival.
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PMID:The 86-kD subunit of Ku autoantigen mediates homotypic and heterotypic adhesion of multiple myeloma cells. 950 80

beta 1 Integrins are considered to be essential for the differentiation of bone-marrow B cells through an interaction with fibronectin-expressed bone-marrow stromal cells. The expression of very late antigens-4 (VLA-4) and -5 (VLA-5) by CD38bright bone-marrow cells in patients with multiple myeloma was measured by flow cytometry using specific monoclonal antibodies. The percentage of CD38bright bone-marrow cells appeared to correlated with that of bone-marrow plasma cells as judged by examination of bone-marrow smears (r = 0.911, P < 0.0001). Expression of VLA-4 and VLA-5 by CD38bright cells varied between patients, but the expression of VLA-4 was always equal to or greater than that of VLA-5. The ratio of VLA-4 to VLA-5 expression (VLA-4:VLA-5 ratio) was calculated and compared with the clinical features of the myeloma patients. A high VLA-4:VLA-5 ratio (> 2.0) was associated with the presence of plasmacytomas and urinary Bence-Jones protein was more common in this group. No other correlations between the clinical features of the disease and the expression of beta 1 integrins were found.
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PMID:Expression of beta 1 integrins (very late antigens-4 and -5) on myeloma cells and clinical correlates in patients with multiple myeloma. 951 75

The very late antigen (VLA)-4 and VLA-5 integrins mediate hematopoietic progenitor cell attachment to bone marrow (BM) stroma. Transforming growth factor-beta1 (TGF-beta1) is a cytokine present in the BM microenvironment that has been shown to regulate the synthesis of adhesion elements in several cell types. We have investigated whether TGF-beta1 action on human BM stromal cells affected the adhesion of progenitor cells involving integrins VLA-4 and VLA-5. Two precursor cell lines, pre-B Nalm-6 and the multipotential UT-7, attached to untreated primary stroma and to the human BM stromal cell line Str-5 preferentially using VLA-4. However, treatment of the stroma with TGF-beta1 resulted in a significant reduction in the participation of VLA-4 in mediating precursor cell adhesion to stroma and a concomitant increase in the utilization of VLA-5. This effect was not exclusive of normal BM stroma. Treatment with TGF-beta1 of stroma from multiple myeloma BM samples produced a substantial increase in VLA-5 use by the myeloma cell line NCI-H929 to adhere to this stroma. The differential use of VLA-4 and VLA-5 correlated with an increase in fibronectin surface expression by stromal cells in response to TGF-beta1. Adhesion assays to purified fibronectin using Nalm-6 cells showed a predominant utilization of VLA-4 at low concentrations of this ligand, whereas higher concentrations resulted in a preferential use of VLA-5. These results indicate that regulation of fibronectin expression on BM stromal cells by TGF-beta1 results in a modulation of the pattern of integrins used by the precursor and myeloma cells to adhere to BM stroma, which could have important consequences on the proliferation and differentiation of hematopoietic precursor cells as well as on the localization and growth of myeloma cells.
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PMID:Differential use of very late antigen-4 and -5 integrins by hematopoietic precursors and myeloma cells to adhere to transforming growth factor-beta1-treated bone marrow stroma. 957 47

Mobilized peripheral blood stem cells (PBSC) are an attractive vehicle for cancer gene therapy. However these stem cells may have a reduced proliferative capacity due to previous cytotoxic chemotherapy treatment of the patient. In addition, primitive hematopoietic stem cells (HSC) from mobilized peripheral blood are almost exclusively quiescent, which makes it hard to induce proliferation in vitro and thus to improve stable transduction of introduced genes into a sufficiently large number of primitive stem cells. In this study CD34-selected mobilized PBSC from lymphoma and myeloma patients were used as target cells for retroviral-mediated gene transfer using a clinically relevant cell- and serum-free supernatant transduction protocol. We have investigated various parameters that may contribute to an improvement of the poor transduction efficiency of the primitive HSC, including prestimulation time, the use of the carboxy-terminal fibronectin fragment CH-296, as well as stromal cell line conditioned media. Retroviral supernatant transduction in combination with CH-296 increased significantly the gene transfer efficiency as compared to supernatant alone and made the use of polycations redundant. Gene transfer of primitive HSC (cobblestone area forming cell (CAFC) week 6) was specifically improved when this procedure was preceded by a 5-day pre-culture period as compared to a 2-day transduction procedure. However, irrespective of the numerical recovery, the CAFC week 6 after retroviral transduction produced less long-term culture colony-forming cells, suggesting a loss of individual stem cell quality. The addition of stroma-conditioned media during the pre-culture period did not affect the individual CAFC quality or transduction efficiency, but increased greatly the recovery of the total number of transduced and untransduced HSC leading to larger grafts containing higher numbers of transduced stem cells.
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PMID:Stroma-conditioned medium and sufficient prestimulation improve fibronectin fragment-mediated retroviral gene transfer into human primitive mobilized peripheral blood stem cells through effects on their recovery and transduction efficiency. 963 25

Multiple myeloma represents a human B cell malignancy which is characterized by a predominant localization of the malignant cell clone within the bone marrow. With the exception of the terminal stage of the disease the myeloma tumor cells do not circulate in the peripheral blood. The bone marrow microenvironment is believed to play an important role in homing, proliferation and terminal differentiation of myeloma cells. Here we have studied the expression of several extracellular matrix (ECM) molecules in the bone marrow of multiple myeloma patients and analyzed their adhesive capacities with four different human myeloma-derived cell lines. All ECM molecules analyzed (tenascin, laminin, fibronectin, collagen types I, III, V and VI) could be detected in bone marrow cryostat sections of multiple myeloma patients. Adhesion assays showed that only laminin, the microfibrillar collagen type VI and fibronectin were strong adhesive components for the myeloma cell lines U266, IM-9, OPM-2 and NCI-H929. Tenascin and collagen type I were only weak adhesive substrates for these myeloma cells. Adhesion to laminin and fibronectin was beta 1-integrin-mediated since addition of anti-beta 1-integrin antibodies could inhibit the binding of the four different cell types to both matrix molecules. In contrast, integrins do not seem to be involved in binding of the myeloma cells to collagen type VI. Instead, inhibition of binding by heparin suggested that membrane-bound heparan sulfate proteoglycans are responsible ligands for binding to collagen type VI. Adhesion assays with several B-cell lines resembling earlier differentiation stages revealed only weak interactions with tenascin and no interactions with collagen type VI, laminin or fibronectin. In summary, the interactions of human myeloma cells with the extracellular matrix may explain the specific retention of the plasma cells within the bone marrow.
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PMID:Adhesive interactions of human multiple myeloma cell lines with different extracellular matrix molecules. 976 71

Throughout the last decades, new developments in cellular and molecular immunology have led to a better insight in the biological nature of MM. Ever since, MM has also been regarded as a tool for studying basic concepts of the terminal B cell differentiation. The first aim of our research work, was to clarify the intraclonal maturation of the tumor clone by examining the existence of myeloma precursor cells at the genetic level. We found that myeloma patients have monoclonal B cells in the peripheral blood and bone marrow which are more immature as the malignant plasma cells and have passed through the stage of antigen selection in the germinal centre. The detection of these myeloma-related cells in the circulation implicates that these cells must be equipped with the appropriate surface receptors that allow transendothelial migration. Once entered in the marrow compartment, the myeloma cells anchor to the stromal environment where they receive the appropriate signals to proliferate and differentiate. We demonstrated that the bone marrow plasma cells express several adhesion molecules that have the potential to interact with stromal elements. We found that myeloma cell lines can bind to fibronectin (FN) and moreover are able to produce FN themselves. Functional assays revealed that FN plays only a minor role in myeloma cell binding to intact stroma, indicating the existence of other and/or multiple adhesive mechanisms. The growth of myeloma cells in the marrow compartment is not only dependent on adhesive interactions but also included the action of locally produced soluble factors. Although IL-6 has been identified as the major growth factor of myeloma cells, maintenance of tumor growth in vivo depends on one or more additional stroma-derived factors. We could establish a unique human myeloma cell line (MM5.1) that grows only in the presence of cultured human bone marrow stroma or stromal conditioned medium and not when cultured with exogeneous IL-6 alone. More recently a stroma-independent variant (MM5.2) of this line was obtained. We found that the growth of MM5.1 cells is mediated by signaling via the gp-130 transducer chain and involves IL-6 acting with a cofactor. The nature of this stromal cofactor is currently under investigation. Both variants of the cell line are also used to study differential expression of genes that are involved in clonal progression towards stroma-independency and extramedullary growth, as can be observed in patients with end stage disease.
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PMID:Homing mechanisms in the biology of multiple myeloma. 980 79

Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selected for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (alpha4beta1) and VLA-5 (alpha5beta1) integrin fibronectin (FN) receptors, are relatively resistant to the apoptotic effects of doxorubicin and melphalan when pre-adhered to FN and compared with cells grown in suspension. This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulation or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with either doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in alpha4-mediated cell adhesion in both drug-resistant variants compared with the drug-sensitive parent line. When removed from selection pressure, drug-resistant cell lines reverted to a drug sensitive and alpha4-low phenotype. Whether VLA-4-mediated FN adhesion offers a survival advantage over VLA-5-mediated adhesion remains to be determined. In conclusion, we have demonstrated that FN-mediated adhesion confers a survival advantage for myeloma cells acutely exposed to cytotoxic drugs by inhibiting drug-induced apoptosis. This finding may explain how some cells survive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression.
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PMID:Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. 1002 95

Clinical features of multiple myeloma are linked with immunological phenotype of myeloma cells. The interactions between malignant plasma cells and proteins of ECM (extracellular matrix) or different cells results from the influence of adhesion molecules. In our study the expression of CD49b, CD49d, CD49e, CD49f on the myeloma cells has been estimated. These cells were obtained from bone marrow of 33 just diagnosed patients. Immunophenotyping was performed with flow cytometry method. Malignant plasma cells were identified by monoclonal antibody anti-CD138 (B-B4) directed against Syndecan-1. We have observed that in patients with high expression of laminin receptors CD49b, CD49f and lack of fibronectin receptors CD49d, CD49e more often renal failure has been confirmed.
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PMID:[The role of beta1 integrins in renal failure accompanied by multiple myeloma]. 1033 38

The integrin VLA-4 mediates attachment of myeloma cells to multiple myeloma (MM) bone marrow stroma. The alternatively-spliced CS-1 region of fibronectin (FN) and VCAM-1 are main ligands for VLA-4 and are both expressed on MM stroma. The H1 region is present in all FN isoforms and represents an additional binding site for VLA-4. We employed FN fragments FN-H89 and FN-H0, that contain either the CS-1 and H1, or only the H1 sites, respectively, as well as soluble VCAM-1 (sVCAM-1), to characterize VLA-4-mediated adhesion pathways used by myeloma cells to attach to MM stroma. CD38highCD45RA- cells from MM bone marrow, and the myeloma-derived cell lines NCI-H929, IM-9 and RPMI 8226, specifically adhered, by different degrees, to FN-H89, FN-H0 and sVCAM-1, and their VLA-4-dependent adhesion was substantially up-regulated by the anti-beta1 antibody TS2/16, which increases the affinity of VLA-beta1 integrins. Furthermore, VLA-4 function on NCI-H929 cells was enhanced by TS2/16 during adhesion to MM stroma. The alpha4beta7 integrin mediated a small portion of myeloma cell line adhesion to FN-H89, mainly upon integrin activation with Mn2+. These results indicate that myeloma cells use VLA-4 to interact with CS-1/FN, H1/FN and VCAM-1 on MM stroma, and that its function can be potentially up-regulated, enabling higher degrees of cell adhesion to these VLA-4 ligands, which might influence myeloma cell localization in the bone marrow.
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PMID:Characterization of VLA-4-dependent myeloma cell adhesion to fibronectin and VCAM-1. 1060 91


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