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

Interleukin-6 (IL-6) is essential for the proliferation of myeloma cells, and IL-6 is considered to be produced from not only myeloma cells themselves but also microenvironments including stromal cells. To clarify which subpopulation of myeloma cells can produce IL-6, we examined IL-6 mRNA expression in immature and mature myeloma cells and normal plasma cells by RT-PCR. IL-6 mRNA expression was found in all (10/10) specimens of sorted VLA-5-MPC-1- immature myeloma cells and 27% (3/11) of VLA-5-MPC-1+ myeloma cells. On the contrary, no IL-6 mRNA was expressed in VLA-5+MPC-1+ mature myeloma cells (0/4) and CD19+CD56- normal plasma cells (0/5). IL-6R gene expression was detected in all normal and malignant plasma cells without exception. Therefore, these findings suggest that IL-6 production is preferentially restricted in immature not mature myeloma cells, and this may explain why immature myeloma cells show greater proliferative activity.
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PMID:Interleukin-6 gene expression is preferentially restricted in VLA-5-MPC-1- immature but not in VLA-5+MPC-1+ mature myeloma cells. 893 35

Myeloma cells consist of immature, intermediate and mature cells with respect to expression of VLA-5 (CD49e) and MPC-1 adhesion molecules. VLA-5(-)MPC-1(-) immature myeloma cells respond to interleukin 6 (IL-6) to proliferate in vitro. but VLA-5+MPC-1+ mature myeloma cells have almost no proliferative activity with higher secretory activity of M-protein in vitro. In order to further clarify the biological differences between these immature and mature myeloma cells, we examined survival of these cells with or without IL-6 in vitro, and investigated the underlying mechanism of the proliferative or non-proliferative character of these cells by examining expression of cell cycle regulators such as cyclin D1 and inhibitors for cyclin-dependent kinase (Cdk), p16INK4A, p21CIP1 and p27KIP1 by RT-PCR and immunohistochemistry. In vitro survival of these myeloma cells was examined by flow cytometric quantification of fluorescein diacetate (FDA) and propidium iodide (PI) staining. Immature myeloma cells rapidly entered apoptosis without IL-6, but mature myeloma cells could survive without IL-6 as well as normal mature plasma cells. Immature myeloma cells as well as myeloma cell lines expressed cyclin D1 mRNA and protein, but not any Cdk inhibitors. On the other hand, mature myeloma cells did not express cyclin D1 but expressed p16, not p21 or p27, as well as normal mature plasma cells. Therefore these results show that immature myeloma cells constitutively express cyclin D1 and can proliferate, and mature myeloma cells as well as normal mature plasma cells preferentially express p16 and can survive for a long time without proliferation.
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PMID:Cyclin D1 and p16INK4A are preferentially expressed in immature and mature myeloma cells, respectively. 935 13

B cells differentiate into plasma cells which produce antibodies in the bone marrow (BM). Multiple myeloma (MM) is a hematologic malignancy in human plasma cells, and myeloma cells grow mainly in BM. According to phenotypic differences, such as expression of adhesion molecules, human myeloma cells as well as normal plasma cells can be classified into several differentiation stages. We have found that cells strongly expressing CD38 antigens (CD38++(+)) in BM are all plasma cells, and that there also are no plasma cells in either CD38- cell fraction or fraction of cells weakly expressing CD38 antigens (CD38+). Myeloma cells in BM consist of CD38++(+)MPC-1-CD49e (VLA-5)-immature and CD38++(+)MPC-1+CD49e+ mature myeloma cells. Immature myeloma cells proliferate markedly in vitro and respond to interleukin-6 (IL-6), a growth factor for myeloma cells, whereas mature myeloma cells show very low proliferative activities and show no response to IL-6. Immature myeloma cells expressing CD21 molecules on their surface seem to attach to stromal cells in BM through binding to CD23 molecules. Thus, there is a heterogeneity in human myeloma cells, and immature myeloma cells appear to proliferate in response to IL-6.
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PMID:Biological significance of heterogeneity in human myeloma cells. 988 36

Using three-colour phenotypic analysis, we detected five subpopulations of myeloma cells (CD38++) in the bone marrow mononuclear cells of human myeloma patients: MPC-1-CD45-CD49e-, MPC-1-CD45+CD49e-, MPC-1+CD45-CD49e-, MPC-1+CD45+CD49e- and MPC-1+CD45+CD49e+. Most of the myeloma cells did not express CD45 but a few MPC-1- immature myeloma cells and some MPC-1+ myeloma cells expressed CD45 and CD45RO but not CD45RA, whereas all of normal early plasma cells in the peripheral blood, lymph node plasma cells and bone marrow plasma cells expressed CD45 and CD45RA, CD45RB but not CD45RO. In order to clarify the biological character of these myeloma subpopulations, we examined the expression of Ki-67 antigen. Proliferating myeloma cells (Ki-67+) were found in the MPC-1- fractions and the MPC-1-CD45+ fractions rather than MPC-1-CD45- fractions. Next, in order to further clarify the biological difference of two immature subpopulations (MPC-1-CD45-CD49e- and MPC-1- CD45+CD49e-), determined cell viability and phenotypic change after culturing with interleukin 6 (IL-6) in vitro. In the presence of IL-6, MPC-1-CD45+ cells kept their viability more than MPC-1-CD45- cells and some MPC-1-CD45- cells could be converted to MPC-1-CD45+ cells. In conclusion, these data suggest that human myeloma cells are phenotypically subdivided into five subpopulations, and among these subpopulations MPC-1-CD45+CD49e- but not MPC-1-CD45-CD49e- immature cells contain proliferating cells in response to IL-6, and IL-6 can also induce expression of CD45 on MPC-1-CD45- subpopulation of immature myeloma cells.
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PMID:MPC-1-CD49e- immature myeloma cells include CD45+ subpopulations that can proliferate in response to IL-6 in human myelomas. 1023 76

A 70-year-old woman presented with monoclonal gammopathy, pancytopenia, and renal insufficiency, which were initially refractory to combination chemotherapy by VMMD (vincristine, ranimustine, melphalan, and dexamethasone) and MP (melphalan and prednisolone) regimens. The myeloma cells, which consisted of 73% of bone marrow nucleated cells, expressed CD38(+), CD19(+), CD56(-), CD45(-), CD49e(-), and MPC-1(+) phenotypes by flow cytometric analysis and showed the rearranged immunoglobulin heavy chain (IgH) gene by Southern blotting. By immunostaining, the myeloma cells were positive for cytoplasmic immunoglobulin light chain kappa. These results suggest that myeloma cells can express CD19(+)CD56(-), the phenotype considered to be expressed on only normal plasma cells.
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PMID:Multiple myeloma expressing CD19(+)CD56(-) phenotype. 1091 86

Multiple myeloma (MM) is a hematologic malignancy of human plasma cells, and myeloma cells can be classified into several subpopulations according to phenotypic differences, such as CD38 MPC-1- CD49e- immature, CD38 MPC-1+ CD49e- intermediate and CD38 MPC-1+ CD49e+ mature myeloma cells. The expression of the CD45 molecule on myeloma cells is quite variable, and the physiological consequence of CD45 on myeloma cells is still unknown. Recently, we have found that a few MPC-1- immature myeloma cells express CD45 antigens while most myeloma cells do not express the CD45. MPC-1- CD45+ CD49e- but not MPC-1- CD45- CD49e- immature cells contain proliferating cells in response to interleukin-6 (IL-6). IL-6 can also induce expression of CD45 on the MPC-1- CD45- subpopulation of immature myeloma cells. In addition, myeloma cell lines responding to IL-6 express CD45, whereas cell lines proliferating independent of IL-6 do not express CD45. In the U266 cell line, IL-6 leads to the induction of CD45 expression and cell proliferation, indicating that IL-6-induced effects are closely linked to CD45 expression. Thus, there is a heterogeneity in human myeloma cells, and among these subpopulations immature myeloma cells expressing the CD45 molecules appear to proliferate in response to IL-6. In this review we propose the involvement of CD45 in MM pathogenesis, and the possible implications of CD45 as both a phenotypic marker and a functional molecule is discussed.
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PMID:Proliferation of immature myeloma cells by interleukin-6 is associated with CD45 expression in human multiple myeloma. 1097 83

Syndecan-1 (CD138) is a cell membrane proteoglycan that binds extracellular matrix components and various growth factors. The role of syndecan-1 in the control of cell growth and morphology has been illustrated by its altered expression in hematological malignancies such as multiple myeloma as well as some solid tumors. It has been reported that the expression of syndecan-1 in cells of the B lineage is developmentally regulated such that pre-B cells and plasma cells express syndecan-1 while mature B cells do not. Thus, we investigated whether the proximal promoter region of the murine syndecan-1 promoter was able to confer the observed on-off-on expression of syndecan-1 in cells of the B lineage as they develop from pre-B cells to plasma cells. Experiments carried out using deletion mutants of the proximal promoter cloned upstream of the CAT reporter gene transfected into murine cell lines, representing the above stages of B-cell development, such as BA/F3 (pro-B cell), 70Z/3 (pre-B cell), 2PK3 (late mature B cell), and MPC-11 (plasma cell), showed detectable levels of CAT expression. The WEHI-231 (mature B cell) cell lines did not show detectable levels of CAT reporter activity. The strong levels of expression were observed with a fragment of the proximal promoter spanning the region from -365 to -95 (from the translation start point). However, Northern analysis of RNA obtained from the five murine B-cell lines, representing various stages of B-cell development, showed that the 70Z/3, MPC-11 but not BA/F3, and 2PK3 cells expressed detectable levels of syndecan-1 mRNA. By FACS analysis, using a rat anti mouse syndecan-1 antibody, syndecan-1 expression on the cell surface was found to correlate with the observed mRNA expression patterns in these cell lines. Our results indicate that the proximal promoter of the murine syndecan-1 promoter is not sufficient for the observed developmental pattern of syndecan expression in B cells.
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PMID:Proximal promoter of the murine syndecan-1 gene is not sufficient for the developmental pattern of syndecan expression in B lineage cells. 1127 53

This study examines the effects of an IL-6-producing murine multiple myeloma cell line on trabecular and cortical mouse bone, and evaluates the efficacy of interleukin-1 receptor antagonist (IL-1ra) in mitigating bone destruction. Six-week-old BALB/c mice were assigned to two groups: normal controls and myeloma animals (5 x 10(7) MPC-11 cells on day 0). Myeloma animals were further assigned to three unique groups: MPC-11 only; MPC-11 treated with hyaluronic acid (HA); and MPC-11 + IL-1ra/HA (100 mg/kg). Disease development was assessed at 14 and 21 days via spleen, liver, and proximal tibia histology; histomorphometry at the femoral middiaphysis; and long bone composition and mechanical testing. Histologic analysis revealed marked myeloma infiltration into organs and bone marrow and gross bone resorption of the proximal tibia. IL-1ra tended to decrease bone resorption at the proximal tibia; however, it had no effect on quantitatively measured bone parameters. Whole femur and tibia, and tibial epiphysis, percent mineralization was decreased (3.0%, 2.9%, and 6.3%, respectively) in all MPC-11 groups. The presence of myeloma did not affect long bone stiffness, strength, or length over the 3 week study. The percent of the femoral endosteal perimeter showing excessive resorption ( approximately 60%) in the MPC-11 groups increased significantly after 21 days. MPC-11 cell presence caused no change in bone formation or morphology. Normal growth mechanisms were not impacted, as the bones lengthened and increased in size and mass despite the presence of myeloma. IL-1 does not appear to be a primary factor in in vivo bone destruction caused by the MPC-11 cell line. These findings reveal the stochastic nature of bone lesions in multiple myeloma and suggest that IL-1 is not a cytokine critical to this disease pathology.
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PMID:Effect of MPC-11 myeloma and MPC-11 + IL-1 receptor antagonist treatment on mouse bone properties. 1179 72

Because tumor-specific antigens have been identified in multiple myeloma (MM), immunotherapy might provide an additional treatment modality for the disease. Expression of CD40 ligand (CD40L) proximate to the MM cells might serve this purpose, either by increasing their capacity to present self-antigens by activation through their CD40 receptor or by the recruitment of professional antigen-presenting cells (APCs) able to take up and present tumor-associated antigens. To distinguish between these possibilities and predict whether human CD40(-) myeloma might respond to this approach, we examined 3 murine plasmacytoma cell lines, 2 (MPC-11 and S107) expressing the CD40 molecule and 1 (X-24) lacking such expression. Syngeneic BALB/CBYJ mice were inoculated subcutaneously with tumor cells mixed with CL7.1 fibroblasts, retrovirally transduced to express either the mCD40L or the neo gene. For all 3 plasmacytoma cell lines, coinjection with CL7.1/mCD40L significantly reduced local tumor growth compared with controls. This effect was mediated by a systemic antitumor immune response, since mice immunized with tumor and CL7.1/mCD40L were resistant to subsequent challenge with tumor, and tumor growth inhibition was abolished when CD8(+) or CD4(+) lymphocytes were depleted. Because expression of CD40L gave equivalent protection from CD40(+) and CD40(-) tumors and transgenic-CD40L failed to up-regulate costimulatory molecules in either tumor, the protective effects of CD40L probably resulted from recruitment/activation of professional APCs rather than from CD40 activation of plasmacytoma cells. As further support of this concept, we found that mice were also well protected if CL7.1 and CD40L were injected together with apoptotic plasmacytoma cells from these tumors. Hence, transgenic CD40L expression may produce an antimyeloma immune response against either CD40(+) or CD40(-) tumors and may be of therapeutic value for both types of myeloma in humans.
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PMID:Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40(+) and CD40(-) plasmacytoma cells. 1207 28

Human myeloma cells are heterogenous morphologically and phenotypically. Myeloma cells can be classified into at least 5 subpopulations; MPC-1-CD45+CD49e-, MPC-1-CD45-CD49e- immature myeloma cells, MPC-1+CD45-CD49e-, MPC-1+CD45+CD49e- intermediate myeloma cells and MPC-1+CD45+CD49e+ mature myeloma cells. Interleukin-6(IL-6) is a major growth factor for human myeloma cells, but only MPC-1-CD45+CD49e- immature myeloma cells can response directly to IL-6 to proliferate. In the U-266 cell lines, IL-6 can lead to the induction of CD45 expression and CD45+ U-266 cells can proliferate in response to IL-6. In primary myeloma cells, MPC-1-CD45-CD49e- immature myeloma cells sorted from bone marrow samples can be changed to CD45+ cells by addition of IL-6 in vitro. In both CD45- and CD45+ U-266 cells, STAT3 and MAPK(ERK1/2) can be activated in response to IL-6 equally between them, but src family kinases such as Lyn, Fyn can be activated only in CD45+ U-266 cells. Thus, the activation of the src family kinases associated with CD45 expression is a prerequisite for the proliferation of myeloma cells. In the bone marrow of myeloma patients, most myeloma cells do not express CD45, and CD45+ immature myeloma cells are only 1 approximately 2%. In order to clarify the difference of cellular context between CD45- and CD45+ myeloma cells, PCR-based cDNA subtraction was performed from CD45+ U-266 cells to CD45-U-266 cells. The series of this subtraction selected several genes. Furthermore, sensitivity to stress stimuli between CD45+ and CD45- U-266 cells was also compared. CD45-U-266 cells were markedly more resistant to stress conditions such as serum-free condition. Therefore, we can speculate that in the bone marrow of human myelomas IL-6 can induce proliferation of CD45+ immature cells, but the amount of IL-6 is too low to support CD45+ myeloma cells and loss of CD45 results in no direct response to IL-6 to proliferate but confers resistance to stress condition leading to the longer survival at the limited amount of IL-6.
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PMID:Growth mechanism of human myeloma cells by interleukin-6. 1243 Aug 75

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