UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiological role of fibronectin (FN) on the human plasma cells were examined using three PC cell lines, FR4ds, OPM1 and OPM1ds. FR4ds was reactive with anti-VLA-alpha 4 and anti-alpha 5. In contrast, OPM1 and OPM1ds were not reactive with anti-VLA-alpha 5. FN induced spreading in FR4ds and OPM1ds. Albumin blocked these spreadings. FR4ds with mature plasma cell phenotype of alpha 4+ and alpha 5+ was more sensitive for FN than OPM1 and OPM1ds with immature phenotype of alpha 4+ and alpha 5-. Spreading cells proliferated more than floating cells. All these cell lines showed chemotaxis toward FN. alpha 5+ FR4ds was more sensitive for FN than OPM1 and OPM1ds with alpha 5- phenotype. These new abilities of PC of spreading and chemotaxis we found are summarized to be an affinity to organs. It is likely that alpha 4+ and alpha 5- PC with low affinity to organs are stored in peripheral blood as a result. We examined the chemotaxtic activity of myeloma cells in bone marrow and these in pleural effusions in a patient with multiple myeloma. These cells in pleural effusions showed more chemotaxic activity than these in bone marrow. FN induced growth, production of Ig, and motility of PC, which resulted in the augmentation of humoral immunity.
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PMID:[Multiple myeloma and adhesion molecules]. 851 Mar 29

Although multiple myeloma (MM) is characterized by a monoclonal expansion of plasma cells, it has been assumed that the tumor clone also includes more immature B cells. We could demonstrate by DNA sequence analysis of the variable region in immunoglobulin (Ig) heavy chain genes, that myeloma patients have peripheral blood monoclonal B cells that have not switched their Ig isotype but are somatically hypermutated. This finding suggests that myeloma originates from a germinal center B cell of the lymph node, most probably a memory B cell or B lymphoblast. The identification of these cells in the peripheral blood circulation implies that they must be equipped with homing receptors that allow them to migrate from the lymph node to the marrow environment. Within the marrow compartment these precursors will receive the appropriate differentiation signals to become mature tumor cells. The growth and survival of these bone marrow (BM) plasma cells is believed to be regulated by a functional interplay with the surrounding marrow stroma involving different adhesive mechanisms and the action of several cytokines. We found that myeloma plasma cells express several adhesion molecules (ICAM-1, N-CAM, CD44, VLA-4). Myeloma cell lines can bind to purified fibronectin (FN) using mostly the VLA-4 receptor. However this interaction contributes only partially to binding with intact stromal layers. In contrast, the post-HDM aplasia was significantly shortened in two of the schedule B patients (3 to 10 days) and was followed by a 25- to 165-fold increase in CD34+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Homing mechanisms in the etiopathogenesis of multiple myeloma. 852 May 7

In most instances, fusion of differentiated cell types with fibroblasts has resulted in the extinction of the differentiation-specific traits of the non-fibroblast parental cell. To explore the genetic basis of this phenomenon, we have studied a series of somatic cell hybrids between mouse myeloma and fibroblasts. All the hybrids were adherent having a fibroblast-like phenotype. Molecular analysis revealed that plasma cell specific genes like the productively rearranged Ig genes, the J chain gene and genes for the cell surface markers CD20 and PC1, were extinguished in the hybrids. In contrast, fibroblast specific genes like fibronectin, alpha 2(I) and III collagens, as well as the receptor for fibroblast growth factor (flg), were expressed. Extinction was not due to chromosomal loss or lack of the relevant genes. To learn about the mechanism(s) of this phenomenon we have looked for the presence of positive and negative transcription factors in our hybrids. Expression of the PU.1 transcription factor, a member of the Ets transcription factor family normally expressed in B cells and macrophages, was lost in the cell hybrids. Interestingly, we found that the B-cell-specific Oct-2 transcription factor was still expressed at somewhat variable levels in several of the hybrid cell lines. In contrast, expression of the recently identified octamer coactivator BOB.1/OBF.1 was extinguished in all cell hybrids. This supports a critical role of this transcriptional coactivator for B-cell-specific gene expression. In addition, the Id and HLH462 genes coding for proteins known to repress bHLH transcription factors by formation of heterodimers, were found to be expressed at increased levels in fibroblasts and in the hybrids, indicating that their increased levels might also contribute to the suppression of myeloma-specific genes. Our results show that in myeloma x fibroblast hybrids, the phenotype of the fibroblast is dominant. It is suggested that fibroblasts contain regulatory "master" genes that are responsible for activation of the fibroblast differentiation pathway and suppress differentiation programs of other cell types.
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PMID:Coordinate suppression of myeloma-specific genes and expression of fibroblast-specific genes in myeloma X fibroblast somatic cell hybrids. 864 90

The chemotaxis of human malignant plasma cells is promoted by two extracellular matrix proteins (ECMs): fibronectin (FN) and laminin (LN). We examined the effect of the supernatant from a bone marrow stroma cell line, KM-101, on the chemotaxis of human malignant plasma cell lines to assess the chemotaxis-regulatory roles of the bone marrow microenvironment. Five human malignant plasma cell lines, FR4ds, OPM-1ds, U266/B1, RPMI-8226 and ARH-77 showed different profiles of the expression of beta 1 integrins of FN and LN receptors. FR4ds, OPM-1ds and U266/B1 cells showed chemotaxis promoted by FN (ChFN) and LN (ChLN). ARH-77 cells showed ChFN but not ChLN. RPMI-8226 cells did not show either ChFN or ChLN. The supernatant from KM-101 cells inhibited the chemotaxis of each of these cell lines regardless of whether the chemotaxis was promoted by FN or LN. Among the cytokines produced by KM-101 cells, it was postulated that IL-6 mediated this inhibitory effect because anti-IL-6 monoclonal antibody (MoAb) and anti-IL-6 receptor MoAb significantly reversed the inhibition. Recombinant IL-6 (rIL-6) also exhibited a similar inhibitory effect. Because anti-gp130 MoAb significantly reversed the chemotaxis inhibitory effect of rIL-6, the inhibitory signal is probably transduced via the signal transducing receptor component, gp130. The chemotaxis-regulatory effect is another previously unrecognized function of this pleiotropic cytokine, IL-6. High levels of IL-6 in the bone marrow microenvironment of patients with multiple myeloma appears to be favourable for the localization of myeloma cells there.
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PMID:Interleukin-6 inhibits the chemotaxis of human malignant plasma cell lines. 865 70

Cell surface-expressed proteoglycans mediate contacts to extracellular matrix (ECM). Human B lymphocytes produce a species of a proteochondroitin sulfate (CSPG) with an approximate molecular mass of 135-150 kDa. Using a monoclonal antibody (mAb) against B cell CSPG in flow cytometry we found that this CSPG is expressed on tumor cells of patients with CD19+ common acute lymphoblastic leukemia and on the corresponding cell lines Nalm-6, Reh and KM3. The CSPG is also present on hairy cell leukemia JOK-1 cells and weakly on the myeloma line U266. Concomitant with CSPG expression, Nalm-6 cells express the integrins alpha 5/beta 1 (CD49e/CD29) and alpha 6/beta 1 (CD49f/CD29), adhesion receptors for fibronectin and laminin, in contrast to the other two cell lines tested. Expression patterns of these adhesion receptors and CSPG were paralleled by strong adhesion of Nalm-6 to fibronectin and laminin. Adhesion of Nalm-6 to fibronectin was inhibited by the alpha 5-specific antibody SAM 1 by 80% whereas the alpha 6-specific antibody GoH3 reduced binding to laminin only by 20%. A possible involvement of surface-expressed CSPG in adhesion to ECM components was investigated by 24 h incubation of Nalm-6 cells with p-nitrophenyl-beta-D-xyloside, an inhibitor of proteoglycan glycosylation. By this treatment, both adhesion of Nalm-6 to laminin and expression of CSPG were reduced by 40-50%. Furthermore, addition of chondroitin-6-sulfate, a structural element of Nalm-6 CSPG, reduced adhesion of Nalm-6 to laminin by 60%. Chondroitin-4-sulfate, heparin and heparan sulfate did not effectively inhibit the adhesion process. These observations suggest that surface-expressed CSPG may be involved in binding of Nalm-6 cells to laminin and that the specific sulfation pattern of chondroitin-6-sulfate may be essential in this regard.
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PMID:Characterization of cell surface-expressed proteochondroitin sulfate of pre-B Nalm-6 cells and its possible role in laminin adhesion. 866 35

The biology of normal plasma cells and the pathophysiology of human multiple myeloma remain poorly understood. Functional assays are scarce and at present cell phenotyping is providing the most information about how human plasma cells may behave. Three different types of human plasma cells: normal, fresh neoplastic myeloma cells and plasma cell lines, have been studied for their reactivity with antibodies to the beta-1 integrins (Very Late Antigens; VLAs), including a panel obtained from the Vth International Workshop on Leucocyte Differentiation Antigens. Most plasma cell targets express VLA-4 (CD49d positive) and the common beta chain recognized by CD29. CD49e (VLA-5) was occasionally positive. Other VLAs were not usually expressed. These data suggest the wide use by plasma cells of VLA-4, possibly as a ligand with fibronectin and high endothelial venules (HEV). Of other adhesion structures expressed by plasma cells, only CD44 is seen as frequently, and this is also a HEV ligand.
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PMID:Very late antigen (VLA) expression by normal and neoplastic human plasma cells; including an assessment of antibodies submitted to the Vth International Workshop on Leucocyte Differentiation Antigens using human myeloma cell lines. 879 96

Long-term bone marrow cultures (LTBMC) were established from marrow samples obtained from 6 myeloma patients and 5 healthy donors and were examined by in situ immunogold-silver staining. During the culture period, the established stroma in myeloma LTBMC revealed a lower level of confluency compared to the normal LTBMC. In addition, an increasing proportion of macrophages and osteoclasts was observed in the myeloma stroma throughout the culture period. Moreover, plasma cells were detectable by wk 8, mostly organized in small clusters. They strongly expressed VLA-4 (6/6), H-CAM (6/6), ICAM-1 (6/6) and N-CAM (3/6). In most cases, a weak expression of the other members of beta 1-integrins was observed. The expression of beta 2-integrins was always absent. Stromal fibroblasts were found to be weakly positive for VLA-2, VLA-3 and VLA-5 and showed strong expression of VCAM-1, H-CAM and ICAM-1. N-CAM expression could not be detected. By comparing the adhesion molecule profile of the stromal cells in myeloma cultures with normal bone marrow (BM) cultures, no particular defects could be observed. The stroma displayed most of the potential ligands which could interact with adhesion molecules detected on the myeloma cells. Among these ligands we could find fibronectin and VCAM-1 for VLA-4, collagen I for VLA-2 and VLA-3 and laminin for VLA-2, 3 and 6. Four myeloma cell lines, i.e. OPM-1, U266, RPMI 8226 and JJN3, with a representative phenotype, were used to study the adhesive interactions of myeloma cells with the BM microenvironment. All the myeloma cell lines bound strongly to the marrow cell layers and also showed a high binding to purified fibronectin (FN). However, the adhesion of the cell lines to intact stroma could not be significantly inhibited by anti-FN receptors antibodies. Nor could it be prevented when the latter were combined with anti-H-CAM, V-CAM and ICAM-1 antibodies, as tested in the JJN3 cell line. This implies that other unknown mechanisms contribute to the myeloma cell binding.
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PMID:Adhesive interactions between tumour cells and bone marrow stromal elements in human multiple myeloma. 900 75

We have earlier described the presence of phenotypically unusual monoclonal B cells within the peripheral blood of multiple myeloma (MM) patients. To determine the biological properties of these B cells as compared to B cells from normal donors, we investigated the potential of CD19+ MM blood B cells to adhere to endothelial cell and bone marrow (BM)-fibroblast monolayers. We find that 30-60% of freshly isolated CD19+ MM blood B cells adhere to endothelial cell monolayers, and 50-80% adhere to BM fibroblast monolayers. The adhesion of MM blood B cells to either monolayer was not increased by in vitro activation, suggesting that these cells were activated in vivo. In contrast, fewer than 10% of CD19+ B cells from peripheral blood of normal donors adhered. Function-blocking monoclonal antibodies (mAbs) were used to determine which adhesion receptors were involved in CD19+ MM blood B cell interaction with BM fibroblasts. mAbs against very late antigen 4, the beta7-integrin subunit, and CD44, but not mAbs against very late antigen 5 and beta1, inhibited adhesion 61, 50, and 30%, respectively. The lack of inhibition with mAbs against beta1 implicates alpha4beta7 but not alpha4beta1 in adhesion of CD19+ MM blood B cells. To determine the alpha4beta7 ligand that mediated MM blood B cell adhesion, mAbs against vascular cellular adhesion molecule 1 and fibronectin, as well as CS1 and RGD peptides, were used as inhibitors. These were unable to reduce the adhesion of CD19+ MM blood B cells to BM fibroblasts, suggesting that fibronectin and vascular cellular adhesion molecule 1 are not involved in adhesion. Also, adhesion of MM blood B cells to mucosal addressin cell adhesion molecule 1-transfected Chinese hamster ovary cells was not enhanced compared to control-transfected Chinese hamster ovary cells, suggesting that mucosal addressin cell adhesion molecule 1 was not promoting adhesion of these cells. These data implicate CD44:HA interactions, as well as alpha4beta7 and an as yet unidentified ligand in the adhesion of in vivo activated MM blood B cell adhesion to BM fibroblasts. The adhesion properties of MM CD19+ B cells distinguishes them from normal B cells. Although the malignant status of these cells is as yet undefined, their adhesion properties implicate MM blood B cells in migratory spread of the disease.
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PMID:Adhesion of multiple myeloma peripheral blood B cells to bone marrow fibroblasts: a requirement for CD44 and alpha4beta7. 904 Nov 97

Recombinant human procollagenase-3 and a C-terminal truncated form (Delta249-451 procollagenase-3) have been stably expressed in myeloma cells and purified. The truncated proenzyme could be processed by aminophenylmercuric acetate via a short-lived intermediate form (N-terminal Leu58) to the final active form (N-terminal Tyr85). The kinetics of activation were not affected by removal of the hemopexin-like C-terminal domain. The specific activities of both collagenase-3 and Delta249-451 collagenase-3 were found to be similar using two quenched fluorescent substrates, but Delta249-451 collagenase-3 failed to cleave native triple helical collagens (types I and II) into characteristic one- and three-quarter fragments. It was noted, however, that the beta1,2(I) chains of type I collagen were susceptible to Delta249-451 collagenase-3, which indicates that the catalytic domain displays telopeptidase activity, thereby generating alpha1,2(I) chains that are slightly shorter than those in native type I collagen. It can be concluded that the C-terminal domain is only essential for the triple helicase activity of collagenase-3. Binding of procollagenase-3 and active collagenase-3 to type I collagen is mediated by the C-terminal domain. Both collagenase-3 and Delta249-451 collagenase-3 hydrolyzed the large tenascin C isoform, fibronectin, recombinant fibronectin fragments, and type IV, IX, X, and XIV collagens; thus, these events were independent from C-terminal domain interactions. In contrast, the minor cartilage type XI collagen was resistant to cleavage. Kinetic analysis of the mechanism of inhibition of wild-type and Delta249-451 collagenase-3 by wild-type and mutant tissue inhibitors of metalloproteinase (TIMPs) revealed that the association rates for complex formation were influenced by both N- and C-terminal domain interactions. The C-terminal domain of wild-type collagenase-3 promoted increased association rates with the full-length inhibitors TIMP-1 and TIMP-3 and the hybrid N.TIMP-2/C.TIMP-1 by a factor of up to 33. In contrast, the association rates for complex formation with TIMP-2 and N.TIMP-1/C.TIMP-2 were only marginally affected by C-terminal domain interactions.
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PMID:The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction. 906 15

The feasibility of ex vivo expansion of hematopoietic progenitors selected from leukapheresis products of patients treated for multiple myeloma (MM) was studied and compared with progenitor expansions from patients with nodular non-Hodgkin's lymphoma (NHL) or healthy donors. After positive selection, CD34+ cells from leukapheresis products of 4 MM and 5 NHL patients and CD34+ cells from bone marrow (BM) of 3 healthy donors were grown in IMDM plus 12.5% horse serum, 12.5% fetal calf serum, IL-1alpha, IL-3, IL-6, SCF, GM-CSF, G-CSF (10 ng/ml each), and EP (4 UI/ml). Outputs of CD34+ cell cultures from MM and NHL patients were similar. Day 14 mean increases in CD34+, CFU-GM, and total cell numbers were, respectively, 5.3-fold, 19.8-fold, and 1173-fold for MM patients and 4.3-fold, 15.6-fold, and 1659-fold for NHL patients, with at least 40% of day 14 cells being of granulocytic lineage. Patient CD34+ cell culture output was found to be related to the CFU-GM/CD34+ cell ratio of selected CD34+ cells, not to underlying pathology. When the initial CFU-GM/CD34+ cell ratio was above 0.025, MM and NHL CD34+ cell culture outputs were always above 1000-fold. Moreover, in all but one CD34+ cell culture, the use of fibronectin (FN)-coated dishes improved CFU-GM and total cell expansion. In patient CD34+ cultures carried out in FN-coated dishes, mean day 14 CFU-GM and total cell outputs were increased, respectively, 2.1-fold and 1.9-fold. We conclude that if the CFU-GM/CD34+ cell ratio is sufficient (>0.025), ex vivo expansion of hematopoietic progenitors from CD34+ cells selected from leukapheresis products is possible for both MM and NHL patients and that using FN-coated flasks is a simple and reliable way to improve both CFU-GM and total cell output.
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PMID:Ex vivo expansion of hematopoietic progenitors from CD34+ cells selected from leukapheresis products of lymphoma and myeloma patients: feasibility and enhancement by fibronectin. 911 56

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