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)

Interleukin-6 (IL-6) is one of the most important growth factors for myeloma cells. We examined the effect of recombinant IL-6 on the proliferation of five human myeloma cell lines, which were independently established AT Kawasaki Medical School. Only the KMS-11 cell line among these five lines showed growth enhancement induced by IL-6. Based on the results, a possible contribution of Ca(2+)-phospholipid-dependent protein kinase C (PKC) to the signal transduction in KMS-11 cells during growth enhancement was studied, since PKC may play an important role in malignant transformation or cell proliferation induced by some growth factors, such as IL-6. When exogenous IL-6 was added to KMS-11 culture, we observed (1) reduction of total PKC activity, and (2) translocation of PKC activity from its cytosol fraction to the membrane fraction. These findings may indicate that down regulation of PKC occurred during the myeloma cell proliferation induced by IL-6. However, IL-6 does not appear to be involved in cell proliferation and differentiation in the other cell lines studied.
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PMID:Down regulation of protein kinase C during growth enhancement induced by interleukin-6 on a human myeloma cell line, KMS-11. 891 77

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 represent a common mechanism of oncogene activation in lymphoid malignancies. In multiple myeloma (MM), the most consistent chromosomal abnormality is the 14q+ marker, which originates in one third of cases through a t(11; 14)(q13; q32) chromosomal translocation; in the remaining cases, the identity of the partner chromosomes has not been well established. We used a Southern blot approach based on the linkage analysis of the joining (J) and the constant (C) mu, alpha, and gamma regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 nonkaryotyped patients with MM (78 cases) or plasma cell leukemia (PCL) (10 cases) and found the presence of "illegitimate" rearranged IGH fragments (no comigration between the J and C regions) in 21 cases. To confirm this analysis, we cloned the illegitimate rearranged fragments from three samples, and the molecular and fluorescent in situ hybridization (FISH) analyses indicated the presence of chromosomal translocations juxtaposing a switch IGH region to sequences from chromosomes 11q13 (one PCL case) or 4p16.3 (two MM cases). Interestingly, the breakpoints on 4p16.3 occurred about 14 kb apart in a genomic region located approximately 50 kb centromeric to the fibroblast growth-factor receptor 3 (FGFR3) gene. Moreover, Southern blot analysis using 4p16.3 genomic probes detected a rearrangement in an additional MM tumor. FISH analysis of the MM-derived KMS-11 cell line, reported to be associated with a t(4; 14)(p16.3; q32), showed that the FGFR3 gene was translocated on 14q32. High levels of FGFR3 mRNA expression were observed in the cloned MM tumors and KMS-11 cell line, but not in the cases that were apparently negative for this lesion. Furthermore, a point mutation at codon 373 in the transmembrane domain of the FGFR3 gene resulting in an amino acid substitution (Tyr --> Cys) was detected in the KMS-11 cell line. These findings indicate that the t(4; 14)(p16.3; q32) represents a novel, recurrent chromosomal translocation in MM, and suggest that the FGFR3 gene may be the target of this abnormality and thus contribute to tumorigenesis in MM.
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PMID:A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. 976 94

A new human myeloma cell line, KMS-18, was established from a 58-year-old male with multiple myeloma associated with hyperammonemia. The original leukemic cells and established KMS-18 cells possessed several of the same chromosomal abnormalities, including add(1)(q32), add(10) (q24) and add(17)(p11). In addition, the KMS-18 cells showed novel t(4;14)(p16.3;q32.3) masked translocation which was determined by the FISH method. Moreover, we compared the ammonia production in culture medium of the KMS-18 cell line with that of non-myeloma hematological malignant cell lines and a hepatocellular carcinoma cell line. KMS-18 produced higher levels of ammonia in medium than the other cell lines examined. This new cell line may prove helpful in analyzing the role and biological mechanisms of the t(4;14)(p16.3;q32.3) translocation in myeloma and also in investigating hyperammonemia in cases with myeloma.
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PMID:Establishment of a new human myeloma cell line, KMS-18, having t(4;14)(p16.3;q32.3) derived from a case phenotypically transformed from Ig A-lambda to BJP-lambda, and associated with hyperammonemia. 947 91

We investigated the effects of MCNU (methyl-6)3-(2-chloroethyl)-3-nitrosoureido)-6-deoxy- alpha-D-glucopyranoside), a nitrosourea anti-tumor agent developed in Japan, on cell growth and differentiation in five human myeloma cell lines and compared it with relative expression levels of MDR-1 gene. Although 10 microg/ml of MCNU inhibited cell growth in KMM-1 and KMS-5 lines, other three cell lines required 20-40 microg/ml of MCNU to obtain similar growth inhibition. Accumulation up to the G2 phase of the cell cycle was observed in KMM-1 and KMS-5 lines and the cloning efficiency of KMS-5 cells was reduced by MCNU. On the other hand, expression of surface markers on these lines was not altered remarkably except for increased expression of CD38 on KMS-5 cells. However, the effect of MCNU on these cell lines did not correlate to relative expression levels of MDR-1 gene analyzed by RT-PCR. MCNU may inhibit the growth of myeloma cells by the accumulation of these cells up to the G2 phase, but may not affect their differentiation.
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PMID:Effect of the nitrosourea anti-tumor chemotherapeutical agent MCNU on five human myeloma cell lines. 962 26

It is well known that cases with multiple myeloma reveal various clinical manifestations such as pancytopenia, hyperproteinemia, renal dysfunction, bone lesions, hypercalcemia and immunodeficiency. Recently, a few more clinical features associated with myeloma, such as salivary type hyperamylasemia and elevated serum C-reactive protein (CRP) concentration, have been reported. The elevation of CRP is thought to be related to interleukin-6 (IL-6) production by myeloma cells, because of identification of IL-6 as an autocrine and/or paracrine growth factor for myeloma cells. More recently, there have been several reports of cases with myeloma associated with hyperammonemia. This hyperammonemia is not considered to be due to liver dysfunction, because in most of these cases tests revealed normal hepatic function, and some cases showed different patterns of serum amino acid distribution than that associated with hepatic failure. However, there have been no apparent observations of ammonia production by myeloma cells. In this study, we used six human myeloma cell lines including KMS-18, which was recently established from a myeloma case associated with hyperammonemia. These lines were treated with MRA (mycoplasma removal agent) to observe ammonia production in vitro. They produced and released significantly higher levels of ammonia into culture medium than non-myeloma hematological cell lines or the HepG2 human hepatic carcinoma cell line. Although attempts to analyze the relative expression levels of the enzymes related to ammonia biosynthesis using the reverse transcriptase-polymerase chain reaction assay failed to detect any differences between these myeloma lines and other cell lines, in vitro excess ammonia production by the myeloma cells was confirmed and the relevance to clinical manifestations is discussed.
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PMID:In vitro excess ammonia production in human myeloma cell lines. 966 3

Although there have been reports regarding the clinical effectiveness of IFN alpha in the treatment of myeloma patients during this decade, its biological effects on human myeloma cells have still not been clarified. Recently, apoptosis has been considered as one of the most important mechanisms in the programmed cell death of malignant tumour cells induced by chemotherapeutic agents or cytotoxic immunological defence in malignancy-carrying hosts. Among the several pathways which function to induce apoptosis, Fas and the Fas ligand system have been thought to play an important role in inducing tumour-cell apoptosis, particularly in immunological prevention. In this study we investigated myeloma cell apoptosis induced by IFN alpha using five human myeloma cell lines which were established without any additional supplementation of IL-6. In addition, the mRNA expression levels of apoptosis-related genes employing the reverse transcriptase-polymerase chain reaction (RT-PCR) were also analysed with the KMS-12-PE cell line, which was the most sensitive of the five cell lines in terms of apoptosis induced by IFN alpha. Based on the results, it was determined that IFN alpha induced myeloma cell apoptosis in a dose-dependent manner, but the sensitivity to IFN alpha in the cell lines examined varied and one cell line revealed growth stimulation by IFN alpha. In addition, the apoptosis induced by IFN alpha did not seem to be mediated by the Fas/Fas ligand pathway. Finally, the IL-6, IL-6R, IRF1 and IRF2 genes were up-regulated in KMS-12-PE cells cultured with IFN alpha. Therefore these genes may play an important role during apoptosis induced by IFN alpha.
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PMID:Human myeloma cell apoptosis induced by interferon-alpha. 982 28

The t(11;14)(q13;q32) chromosomal translocation, which is the hallmark of mantle cell lymphoma (MCL), is found in approximately 30% of multiple myeloma (MM) tumors with a 14q32 translocation. Although the overexpression of cyclin D1 has been found to be correlated with MM cell lines carrying the t(11;14), rearrangements of the BCL-1/cyclin D1 regions frequently involved in MCL rarely occur in MM cell lines or primary tumors. To test whether specific 11q13 breakpoint clusters may occur in MM, we investigated a representative panel of primary tumors by means of Southern blot analysis using probes derived from MM-associated 11q13 breakpoints. To this end, we first cloned the breakpoints and respective germ-line regions from a primary tumor and the U266 cell line, as well as the germ-line region from the KMS-12 cell line. DNA from 50 primary tumors was tested using a large panel of probes, but a rearrangement was detected in only one case using the KMS-12 breakpoint probe. Our results confirm previous findings that the 11q13 breakpoints in MM are scattered throughout the 11q13 region encompassing the cyclin D1 gene, thus suggesting the absence of 11q13 breakpoint clusters in MM.
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PMID:Molecular analysis of 11q13 breakpoints in multiple myeloma. 994 76

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 represent a common mechanism of oncogene activation in lymphoid malignancies. In multiple myeloma (MM), variable chromosome partners have been identified by conventional cytogenetics, including the 11q13, 8q24, 18q21, and 6p21 loci. We and others have recently reported a novel, karyotypically undetectable chromosomal translocation t(4;14)(p16. 3;q32) in MM-derived cell lines, as well as in primary tumors. The 4p16.3 breakpoints are relatively scattered and located less than 100 kb centromeric of the fibroblast growth factor receptor 3 (FGFR3) gene or within the recently identified WHSC1 gene, both of which are apparently deregulated by the translocation. To assess the frequency of the t(4;14)(p16.3;q32) translocation in MM, we performed a double-color fluorescent in situ hybridization (FISH) analysis of interphase nuclei with differently labeled probes specific for the IGH locus (a pool of plasmid clones specific for the IGH constant regions) or 4p16.3 (yeast artificial chromosome (YAC) 764-H1 spanning the region involved in breakpoints). Thirty MM patients, the MM-derived cell lines KMS-11 and OPM2, and six normal controls were examined. The identification of a t(4;14) translocation, evaluated as the presence of a der(14) chromosome, was based on the colocalization of signals specific for the two probes; a cutoff value of 15% (mean + 3 standard deviation [SD]) derived from the interphase FISH of the normal controls (range, 5% to 11%; mean +/- SD, 8.16 +/- 2.2) was used for the quantification analysis. In interphase FISH, five patients (one in clinical stage I, two in stage II, one in stage III, and a plasma cell leukemia) were found to be positive (approximately 15%). FISH metaphases with split or colocalized signals were detected in only two of the translocated cases and confirmed the pattern found in the interphase nuclei. Furthermore, in three of the five cases with the translocation, FISH analysis with the IGH joining probe (JH) showed the presence of the reciprocal product of the translocation [der(4) chromosome]. Overall, our study indicates that the t(4;14)(p16. 3;q32) chromosomal translocation is a recurrent event in MM tumors and may contribute towards the detection of this lesion and our understanding of its pathogenetic and clinical implications in MM.
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PMID:Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by double-color fluorescent in situ hybridization. 1039 39

In multiple myeloma (MM), the cell surface protein, CD19, is specifically lost while it continues to be expressed on normal plasma cells. To examine the biological significance of loss of CD19 in human myeloma, we have generated CD19 transfectants of a tumorigenic human myeloma cell line (KMS-5). The CD19 transfectants showed slower growth rate in vitro than that of control transfectants. They also showed a lower capability for colony formation as evaluated by anchorage-independent growth in soft agar assay. The CD19 transfectants also had reduced tumorigenicity in vivo when subcutaneously implanted into severe combined immunodeficiency (SCID)-human interleukin-6 (hIL-6) transgenic mice. The growth-inhibitory effect was CD19-specific and probably due to CD19 signaling because this effect was not observed in cells transfected with a truncated form of CD19 that lacks the cytoplasmic signaling domain. The in vitro growth-inhibitory effect was confirmed in a nontumorigenic human myeloma cell line (U-266). However, introduction of the CD19 gene into a human erythroleukemia cell line (K-562) also induced growth inhibition, suggesting that this effect is CD19-specific, but not restricted to myeloma cells. These data suggest that the specific and generalized loss of CD19 in human myeloma cells could be an important factor contributing to the proliferation of the malignant plasma cell clones in this disease.
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PMID:Enforced CD19 expression leads to growth inhibition and reduced tumorigenicity. 1055 66

Recently several chromosomal translocations involved in myeloma cases and myeloma cell lines; i.e., t(11;14)(q13;q32), t('8;14)(q24;q32), t(4;14)(q16.3;q32.3), t(6;14)(p25;q32), and t(14;16)(q32.3;q23), have been identified. These translocations are considered to dysregulate genes which may be concerned with myelomagenesis; i.e., PRAD1/cyclin D1, the c-myc oncogene, FGFR3 (fibroblast growth factor receptor 3), MMSET (multiple myeloma SET domain), MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4), and the c-maf oncogene, respectively. However, the cellular biological roles of these genes have not yet been elucidated in myeloma cells. Because two of the seven human myeloma cell lines which were established at Kawasaki Medical School, Okayama, Japan, KMS-11 and KMS-18, have been proven to possess t(4;14)(q16.3;q32.3), we studied the expression levels of the FGFR3 gene in these seven cell lines and 13 primary myeloma specimens. The expression levels of 12 known FGF family genes (FGF-1 to 12) and 4 FGFR genes (FGFR1 to 4) were also examined in seven cell lines. In addition, the growth status of the KMS-11 and KMS-18 lines with FGF-1 or anti-FGF-4 neutralizing monoclonal antibody (MoAb) supplementation was investigated because FGF-1 and 4 are known as the principal ligands for FGFR3. FGFR3 overexpression was observed in both of the cell lines possessing t(4;14)(q16.3;q32.3) and in 3 of 13 case specimens. Anti-FGF-4 neutralizing MoAb caused significant growth inhibition in these two cell lines possessing t(4;14)(q16.3;q32.3). These findings indicate that t(4;14) (q16. 3;q32.3) may provide myeloma cells with a growth advantage via an autocrine mechanism between FGFR3 and FGF-4.
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PMID:Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation. 1056 29


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