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)

In order to elucidate the pathologic significance of the bone marrow (BM) microenvironment in multiple myeloma (MM) and rheumatoid arthritis (RA), we established patient- or healthy donor (HD)-derived BM stromal cell lines by transfecting the plasmid for expression of SV40 large T Ag and examined their ability to support the stromal cell-dependent growth of a pre-B cell line, DW34. The means of recovered cell numbers of DW34 co-cultured with MM- and RA-derived BM stromal cell lines ranged from 6- to 10-fold more than those with HD-derived ones. Their enhanced ability to support DW34 cell growth was not caused by cytokines, including IL-6, IL-7, and c-kit ligand, although exogenous IL-7 could augment the growth-supporting ability. DW34 cell growth on the stromal cell lines was abolished by inhibiting cell-to-cell interaction with a membrane filter. FACS analysis revealed that the stromal cell lines did not express LFA-1 alpha, beta, NCAM, or ELAM-1. Both patient and HD BM stromal cell lines variably expressed ICAM-1, VCAM-1, and CD44. However, surface expression levels of these molecules did not correlate with the ability of the stromal cell lines to support DW34 cell growth. Taken together, these results suggested that BM microenvironment might play important roles in the pathogenesis of MM and RA.
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PMID:Human bone marrow stromal cell lines from myeloma and rheumatoid arthritis that can support murine pre-B cell growth. 128 Dec 1

Engagement of the cell surface receptor for interleukin 7 (IL-7R) provokes protein tyrosine phosphorylation, although the receptor lacks a kinase catalytic domain in its cytoplasmic tail. The molecular basis of this response is not known. Here we report that the IL-7R functions by recruiting p59fyn, an intracellular tyrosine kinase of the src family. Treatment of pre-B cells with IL-7 causes an enhancement of the catalytic activity of p59fyn, but not of the related kinase p62yes. IL-7-dependent stimulation of the enzyme phosphatidylinositol 3-kinase, a tyrosine kinase substrate, provides further evidence suggestive of p59fyn activation. We demonstrate that p59fyn forms part of a protein complex with the IL-7R. A chimeric receptor comprising the CD8 extracellular domain and the IL-7R cytoplasmic tail (CD8/IL-7R) recruits tyrosine kinase activity in transfected myeloma cells, and p59fyn can be detected in association with it by immunoprecipitation and immunoblotting. Conversely, p59fyn immunoprecipitates contain the phosphorylated CD8/IL-7R. We have identified a segment of the IL-7R cytoplasmic tail which mediates p59fyn recruitment: a truncated CD8/IL-7R containing only this segment recruits tyrosine kinase activity, associates with p59fyn, and activates phosphatidylinositol 3-kinase. Interestingly, this segment contains no tyrosine residues, although it is the phosphotyrosine-binding src homology domains of p59fyn and phosphatidylinositol 3-kinase which mediate their association with many growth factor receptors. Thus our results suggest that an unusual interaction links IL-7R to these two important signaling pathways.
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PMID:Interleukin 7 receptor functions by recruiting the tyrosine kinase p59fyn through a segment of its cytoplasmic tail. 146 44

Soluble forms of the interleukin (IL)-2, IL-4 and IL-7 receptors which lack the transmembrane domain have been described. IL-6 is a growth factor important in the final differentiation of B-cells into plasma cells and in the pathogenesis of multiple myeloma. To determine whether the receptor for IL-6 may exist as a soluble molecule, RNA was analysed from the transformed B-cell lines U266, CESS and Daudi, from bone marrow from two myeloma patients, and from normal leukocytes. Using polymerase chain reaction, oligonucleotide primers which flank the transmembrane domain were selected to generate a 339 bp fragment. All samples produced equivalent amounts of the expected 339 bp fragment plus a smaller 245 bp fragment except Daudi which exhibited virtual absence of both. Sequence analysis of the smaller fragments from each of the five samples demonstrated the deletion of the entire transmembrane region from codons 356 (G-TG) to 387 (AG-G). The boundaries of this deletion were identical in all cases. Partial sequence analysis of the ligand-binding domain for U266 demonstrated identical sequences for the membrane-bound and soluble forms of the IL-6 receptor cDNAs. In summary, an mRNA which encodes a soluble form of the IL-6 receptor is expressed in both normal and myeloma cells.
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PMID:Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. 163 65

Multiple myeloma (MM) is a slow-growing malignancy whose plasma cells express the BCL-2 antiapoptosis gene. It is also associated with high levels of interleukin-6 (IL-6), a cytokine that prevents programmed cell death (PCD) in other target cell types. We thus investigated the ability of MM cells to undergo PCD and the possible regulatory effects of IL-6. Four MM cell lines underwent PCD when exposed to serum starvation, doxorubicin (dox), etoposide (VP-16), or dexamethasone (dex). Apoptosis was confirmed by morphologic criteria and/or detection of endonucleosomal DNA fragmentation. The concentrations of dox, VP-16, and dex required for PCD were at least 10-fold greater than that required to inhibit proliferation. Addition of IL-6 (but not IL-1 beta, IL-4, IL-7, or IL-10) inhibited PCD of 8226 targets induced by serum starvation or dexamethasone in a concentration-dependent fashion. In contrast, it had no effect on PCD induced by dox or VP-16. Exposure of targets to IL-6 did not increase BCL-2 expression (it actually consistently decreased expression), suggesting IL-6's protection against apoptosis was not mediated by direct effects on BCL-2. Targets protected from PCD by IL-6 were still sensitive to serum starvation and dex-induced cytostasis, but, after reculturing in drug-free complete media, they reinitiated normal proliferation. These data suggest that high levels of IL-6 may contribute to expansion of myeloma clones by inhibiting apoptotic death.
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PMID:Interleukin-6 inhibits apoptosis of malignant plasma cells. 774 52

Follicular dendritic cells (FDC) are specialized cells residing primarily within lymphoid follicles. They bind immunocomplexes and play an important role in the presentation of antigen to follicular B cells. Isolation of FDC for in vitro studies, however, is difficult because they constitute only about 1% of the cells in lymphoid tissue and form tight clusters entrapping lymphocytes within their dendritic processes. The monoclonal antibody (mAb) Ki-M4, which is highly restricted in its binding to FDC, is used to identify these cells. In order to establish a new immortalized cell line with features of FDC, we applied a modified procedure to isolate and enrich FDC from human tonsils and fused them with the myeloma cell line SP2/0-Ag14. The new hybrid cell line, designated FDC-H1, is of both mouse lymphoid and human FDC origin. FDC-H1 was found to have unlimited growth potential and to consistently express the Ki-M4 antigen and other surface antigens of human FDC. Semiquantitative reverse-transcribed polymerase chain reaction (RT-PCR) of enriched FDC and FDC-H1 revealed the same highly restricted cytokine/mRNA profile for both, with detectable levels of interleukin (IL)-1 alpha and surface CD23 and a lack of mRNA for IL-1 beta, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta and granulocyte/macrophage-colony-stimulating factor. Additionally a weak but constant IL-6 mRNA expression was found in the cell line FDC-H1 by RT-PCR. In situ hybridization experiments in tonsils revealed IL-6 transcripts in cells with a staining pattern characteristic of a dendritic cell only in a few germinal centers. To our knowledge, FDC-H1 is the first cell line that constantly expresses surface antigens and a cytokine profile characteristic of FDC. It is, therefore, well suited for studying the biology of FDC and the functional relationship between FDC and normal or neoplastic lymphatic cells.
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PMID:An immortalized cell line with features of human follicular dendritic cells. Antigen and cytokine expression analysis. 795 61

mAbs specific for mouse lambda 5 protein were prepared by fusion of spleen cells from a hamster immunized with recombinant lambda 5 protein synthesized in bacteria and the mouse myeloma cell line SP2/0-Ag14. Here we report the characteristics of the antibodies produced by the FS1 hybridoma. FS1 antibody stains a variety of mouse pre-B cell lines but not B cell lines or T cell lines. The staining of the pre-B cell lines A-1 and C-7 by phycoerythrin (PE)-conjugated FS1 (FS1-PE) can be blocked by preincubation of these cells with unconjugated FS1 antibody or with affinity purified polyclonal lambda 5 specific Ig but not with normal hamster or mouse IgG or with affinity purified polyclonal anti-Mb-1 Ig. From these experiments we concluded that FS1 specifically recognizes lambda 5 protein. We used FS1-PE to probe for surface (s) lambda 5+ cells in normal BALB/c mouse bone marrow. Such cells were undetectable when total bone marrow or FACS sorted subpopulations were analyzed. However, when B220+, CD43+, s lambda 5-bone marrow cells were cultured for 4 days on the stromal cell line FLST2 in the presence of IL-7, s lambda 5 expression became apparent. Further expansion of these cells in IL7 alone augmented the s lambda 5 expression to readily detectable levels. This modulation may indicate that s lambda 5 expression on normal bone marrow cells in vivo is transient and that at any given moment only a small fraction of bone marrow cells expresses low levels of lambda 5 protein on the surface.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoclonal anti-lambda 5 antibody FS1 identifies a 130 kDa protein associated with lambda 5 and Vpre-B on the surface of early pre-B cell lines. 818 91

We have investigated which of the cytokines that are relevant in the in vitro growth of multiple myeloma (MM) malignant plasma cells are actually produced in vivo by MM patients. To this end, we have measured the levels of IL-1 beta, IL-3, IL-4, IL-6, IL-7, IL-8 and tumour necrosis factor-alpha (TNF-alpha) both in sera and in the supernatant of bone marrow (BM) stromal cell cultures from patients with MM and monoclonal gammopathy of undetermined significance (MGUS). The significance of our findings is three-fold. First, IL-6 and IL-8 are produced by MM BM stromal cells, while IL-1 beta, TNF-alpha, IL-4 and IL-7 are not. Second, IL-3 is the only cytokine consistently raised in serum samples: we have also detected low levels of serum IL-6 in a minority of cases, usually in advanced stage of the disease. Third, MM BM stromal cells are active IL-6 and IL-8 producers, while both normal and MGUS BM stromal cells are low producers, thus suggesting that in the BM of MM a number of environmental cells, that would normally be quiescent, are instead activated and that, in MM, activated BM stromal cells play an active role in supporting the progressive expansion of the B cell clone.
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PMID:Cytokines involved in the progression of multiple myeloma. 846 62

Recent investigations of the cytokine network surrounding myeloma cells have disclosed the importance of gp130-related cytokines including interleukin (IL)-6 for myeloma cell survival and proliferation, identification of IL-10 as a growth factor for myeloma cells, the close relationship between IL-10 and the receptors for gp130-related cytokines, and the growth enhancement effect of IL-11 and IL-7 on myeloma cells. In this study, IL-10 production was observed in three out of seven human myeloma cell lines examined and five (including three producing lines) out of 10 lines exhibited mRNA expression of IL-10. The IL-10 mRNA expression was also enhanced in approximately one third of primary specimens, whereas the IL-10 receptor (R) expression was not changed compared with that of normal component marrow controls. However, reverse transcription-polymerase chain reaction (RT-PCR) assay of various cytokines and their receptors showed no particular association with IL-10-producing myeloma lines compared with non-producing lines. Supplementing exogenous IL-10 or neutralization of the IL-10 signal by anti-IL-10 monoclonal antibody (mAb) in a culture conditions did not significantly affect myeloma cell growth regardless of expression of IL-10 or its receptor (IL-10R). However, supplement of anti-IL-10 mAb caused upregulation of certain genes such as IL-11, leukaemia inhibitory factor receptor (LIFR) and syndecan-1 in IL-10R-expressing cell lines. These findings indicate that the cytokine network surrounding myeloma cells is complicated and variable. In addition, IL-10 may modify this network and the cellular biological properties of myeloma cells rather than cell proliferation.
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PMID:Expression and production of interleukin 10 in human myeloma cell lines. 1112 45

Translocations involving fibroblast growth factor receptor 3 (fgfr3) have been identified in about 25% of patients with myeloma. To directly examine the oncogenic potential of fgfr3, murine bone marrow (BM) cells were transduced with retroviral vectors containing either wild-type fgfr3 or an activated mutant form of the receptor, fgfr3-TD. Mice transplanted with FGFR3-TD-expressing BM developed a marked leukocytosis and lethal hematopoietic cell infiltration of multiple tissues within 6 weeks of transplantation. Secondary and tertiary recipients of spleen or BM from primary fgfr3-TD mice also developed tumors within 6 to 8 weeks. Analysis of the circulating tumor cells revealed a pre-B-cell phenotype in most mice, although immature T-lymphoid or mature myeloid populations also predominated in some animals. Enhanced lymphoid but not myeloid colony formation was observed in the early posttransplantation period and only interleukin 7 and FGF-responsive pre-B-cell lines could be established from tumors. Cell expansions in primary recipients appeared polyclonal, whereas tumors in later passages exhibited either clonal B- or T-cell receptor gene rearrangements. Mice transplanted with wild-type FGFR3-expressing BM developed delayed pro-B-cell lymphoma/leukemias approximately 1 year after transplantation. These studies confirm that FGFR3 is transforming and can produce lymphoid malignancies in mice.
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PMID:The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells. 1129 Jun 5

Previous studies identified CD56(+) and CD56(-) subsets of peripheral gamma delta T cells from healthy donors. Both subsets responded to stimulation by a myeloma cell line, XG-7 and undergo vigorous ex vivo expansion in the presence of exogenous IL-2. They are cytotoxic for different tumor targets including nasopharyngeal carcinoma, but they differ from one another in that the CD56(-) subset has an additional growth requirement for IL-7 and exhibited greater cytotoxicity against nasopharyngeal carcinoma (NPC) targets. These immune cells were further shown to retard tumor growth in a nude mice NPC model. To assess if these immune cells might contribute to host defense against NPC, we compared gamma delta T-cell status of NPC patients with healthy donors and survivors who had been in clinical remission of the cancer. It was found that peripheral gamma delta T cells of patients were impaired in their response to the stimulatory effects of XG-7 and exhibited weak or essentially no cytotoxicity for the NPC targets. The deficits were present in early and advanced stages of the cancer but were restored among survivors after successful treatment of the cancer. These findings support a role for peripheral gamma delta T cells in host defense against NPC. It was noted that these immune cells comprise less than 5% of peripheral blood monocytic cells and hence it was not surprising that this component of host defense was breached early in the development of the cancer.
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PMID:Peripheral gamma delta T-cell deficit in nasopharyngeal carcinoma. 1197 36


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