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)

Through the application of the NIH/3T3 tumorigenicity assay to DNA from a gastric carcinoma, we have identified a novel transforming gene, designated myeov (myeloma overexpressed gene in a subset of t[11;14]-positive multiple myelomas). Sequence analyses did not reveal any homology with sequences present in the GenBank, except the deduced protein structure predicts a transmembrane localization. Myeov was mapped to chromosome 11q13 and localized by DNA fiber fluorescence in situ hybridization (FISH) 360-kilobase (kb) centromeric of cyclin D1. In 3 of 7 multiple myeloma (MM) cell lines with a t(11;14)(q13;q32) and cyclin-D1 overexpression, Northern blot analysis revealed overexpression of myeov as well. In all 7 cell lines, the translocation breakpoint was mapped within the 360-kb region between myeov and cyclin D1. DNA fiber FISH with a contig of probes covering the constant region of the immunoglobulin heavy chain (IgH) revealed that exclusively in the 3 myeov-overexpressing cell lines (KMS-12, KMS-21, and XG-5), either the 5' E(mu) enhancer or the most telomeric 3' Ealpha enhancer was juxtaposed to myeov. Although cyclin D1 overexpression represents a characteristic feature of all MM cell lines with t(11;14), our results demonstrate aberrant expression of a second putative oncogene in a subset of these cases, due to juxtaposition to IgH enhancers. The clinical relevance of this dual activation remains to be elucidated. (Blood. 2000;95:2691-2698)
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PMID:Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32). 1075 52

Bone morphogenetic proteins (BMPs), members of the transforming growth factor (TGF)-beta superfamily, are a group of related proteins that are capable of inducing the formation of cartilage and bone but are now regarded as multifunctional cytokines. We show in this report a novel function of BMPs in hematopoietic cells: BMP-2 induces apoptosis not only in human myeloma cell lines (U266, RPMI 8226, HS-Sultan, IM-9, OPM-2, and KMS-12 cells), but also in primary samples from patients with multiple myeloma. The mechanism of BMP-2-induced apoptosis was investigated with the use of U266 cells, which are dependent on the interleukin-6 autocrine loop. We showed that BMP-2 caused cell-cycle arrest in the G1 phase and the subsequent apoptosis of myeloma cells. BMP-2 up-regulated the expression of cyclin-dependent kinase inhibitors (p21(CIP1/WAF1) and p27(KIP1)) and caused hypophosphorylation of retinoblastoma (Rb) protein. In studies of apoptosis-associated proteins, BMP-2 was seen to down-regulate the expression of Bcl-x(L); however, BMP-2 had no effects on the expression of Bcl-2, Bax, or Bad. Therefore, BMP-2 induces apoptosis in various human myeloma cells by means of the down-regulation of Bcl-x(L) and by cell-cycle arrest through the up-regulation of p21(CIP1/WAF1) and p27(KIP1) and by the hypophosphorylation of Rb. Further analysis showed that the signal transducer and activator of transcription 3 (STAT3) was inactivated immediately after BMP-2 treatment. We conclude that BMP-2 would be useful as a novel therapeutic agent in the treatment of multiple myeloma both by means of its antitumor effect of inducing apoptotis and through its original bone-inducing activity, because bone lesions are frequently seen in myeloma patients.
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PMID:Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. 1097 40

To clarify cellular biological varieties of myeloma cells, biological differences were analyzed between 2 human myeloma cell lines, KMS-12-PE and KMS-12-BM, derived from pleural effusion and bone marrow, respectively, of a single patient. Although both lines were considered to be derived from the same clone because both had the same chromosomal marker and immunoglobulin H rearrangement, several biological differences were noted. CD11a and CD20 were highly expressed in the KMS-12-BM line, whereas the KMS-12-PE line showed a higher expression of CD7 and CD95/Fas. Although growth was stimulated in KMS-12-BM by interleukin-6 and interferon-alpha, it was inhibited in KMS-12-PE. In addition, apoptosis inhibitors Bcl-2 and Bcl-X(L) were highly expressed in KMS-12-BM cells. Because KMS-12-PE was cultivated 2 months before KMS-12-BM, these differences might be related to their origin (pleural effusion and bone marrow) or the phases of disease progression. However, these biological differences may help clarify myeloma cell biology and lead to improvement in treatment for myeloma patients.
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PMID:Cellular biological differences between human myeloma cell lines KMS-12-PE and KMS-12-BM established from a single patient. 1103 72

Conditionally replicating viruses are promising agents for the treatment of malignancy. Here it is shown that the live attenuated Edmonston-B vaccine strain of measles virus (MV-Edm) replicates selectively in human myeloma cells and has potent antitumor activity. In vitro, replication of MV-Edm was restricted in phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs) but proceeded efficiently in a panel of 6 myeloma cell lines-ARH-77, RPMI 8226, JJN-3, MM1, KAS-6/1, and KMS-11-and in primary myeloma cells isolated by CD138 sorting from the bone marrow aspirates of 6 patients. MV-Edm infection induced potent cytopathic effects in these myeloma cells, resulting in the formation of multinucleated syncytia that eventually became nonviable. In contrast, syncytial formation in PHA-stimulated PBLs was minimal after MV-Edm infection. In vivo, MV-Edm was antitumorigenic and inhibited the establishment of myeloma cells as xenografts in immunocompromised mice. When injected directly into ARH-77 myeloma xenografts in the mice, MV-Edm caused complete regression of these xenografts. MV-Edm administered intravenously into the tail veins of mice also showed significant antineoplastic activity against established RPMI 8226 and ARH-77 xenografts. In particular, the ARH-77 myeloma xenografts were exquisitely sensitive to MV-Edm therapy, and tumors in all mice regressed completely. In light of its selectivity for myeloma cells and its potent antineoplastic activity against myeloma xenografts in vivo, MV-Edm merits further development for the treatment of multiple myeloma.
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PMID:Systemic therapy of myeloma xenografts by an attenuated measles virus. 1156 82

CD27 is a marker of memory B cells and its interaction with its ligand, CD70, is very important for differentiation into plasma cells. Although CD27 is detected on normal plasma cells, its expression is significantly reduced with the progression of multiple myeloma (MM), including monoclonal gammopathy of undetermined significance (MGUS). CD27+ myeloma cells are thought to represent an early phase of myeloma, as CD27+ plasma cells from MM patients were found to be composed of normal plasma cells (CD19+/CD38++) and myeloma cells (CD19-/CD38++), and monoclonality was detected in the CD27+/CD38++ fraction. Given that the lack of CD27 on plasma cells is related to myelomagenesis and that the pro-apoptotic protein Siva is thought to bind to the cytoplasmic tail of CD27, we analysed alterations of cell growth and genes caused by co-culturing CD27-transfected myeloma cell lines (U266, KMS-5) with CD70-transfected NIH3T3 cells. CD27-CD70 interaction could not induce apoptosis in either type of myeloma transfectant, and binding between Siva and CD27 was not detected. cDNA microarray (human apoptosis CHIP) analysis showed a significant upregulation of expression of the ectodermal neural cortex 1 (ENC1) gene by CD27-CD70 interaction compared with CD27 transfection alone. These findings show that the relationship between the loss of CD27 and oncogenesis of plasma cells is not simple. It remains unclear whether the lack of CD27 leads to evasion of apoptosis.
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PMID:A possible role for the loss of CD27-CD70 interaction in myelomagenesis. 1254 79

Chromosomal rearrangements of the MYC locus, which often involve the IG loci, are recurrent events in multiple myeloma (MM) and plasma cell leukemia (PCL). We used dual-color fluorescence in situ hybridization (FISH) to characterize the breakpoint locations of chromosomal translocations/rearrangements involving the MYC locus at 8q24 found in a panel of 14 MM cell lines and 70 primary tumors (66 MM and 4 PCL). MYC locus alterations were observed in 21 cases: MYC/IG (mainly IGH@) fusions in 11 cell lines and three patients (2 MM and 1 PCL), and extra signals and/or abnormal MYC localizations in seven patients (5 MM and 2 PCL). Fourteen of these cases were investigated by FISH analyses by use of a panel of BAC clones covering about 6 Mb encompassing the MYC locus. The breakpoints were localized in a region 100-250 kb centromeric to MYC in four cases, a region 500-800 kb telomeric to the gene in four cases, and regions > or = 2 Mb centromeric or telomeric to MYC in five cases. Two different breakpoints were detected in the KMS-18 cell line, whereas the insertion of a MYC allele was found in a complex t(16;22) chromosomal translocation in the RPMI8226 cell line. Our data document a relatively high dispersion of 8q24 breakpoints in MM.
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PMID:Heterogeneous pattern of chromosomal breakpoints involving the MYC locus in multiple myeloma. 1275 24

Although recent developments in initial chemotherapeutic regimens and stem cell transplantation have achieved improvements of initial remission for myeloma patients, relapse and recurrence are still major problems. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been developed for treating hyperlipidemia. Recently, there have been several reports concerning the effects of statins on cancer cells including liver, colon, leukemia, malignant B, stomach, and breast cells. In this study, the in vitro effects of pravastatin on human myeloma cells and the factors closely related to its growth inhibitory effects were examined. Although concentrations were higher than those used clinically, 4 out of 10 myeloma lines showed growth inhibition by pravastatin. The study of factors related to the inhibition indicated IL-6 is important. Indeed, rhIL-6 abolished pravastatin-induced growth inhibition in KMS-21BM cells which did not express IL-6. Statins may be useful in maintenance therapy for myeloma after the screening of IL-6 status.
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PMID:IL-6 is a key factor in growth inhibition of human myeloma cells induced by pravastatin, an HMG-CoA reductase inhibitor. 1288 15

Ginseng (the root of Panax ginseng C.A. Meyer, Araliaceae) has been used as a crude drug taken orally for preventive and therapeutic purposes in Asian countries as a traditional medicine. In the current study, we have investigated the antitumor effect of a novel ginseng protopanaxadiol saponin bacterial metabolic derivative, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (IH-901), in eight human myeloma cell lines. IH-901 inhibited the proliferation of all myeloma cell lines examined. Despite the fibroblast growth factor receptor 3 (FGFR3) overexpression due to a chromosomal translocation t(4;14)(q16.3;q32.3) in KMS-11 myeloma cells, IH-901 induced apoptosis in a dose- and time-dependent way in this cell line. Treatment of KMS-11 with IH-901 resulted in the formation of internucleosomal DNA fragments, poly (ADP-ribose) polymerase cleavage, and the activation of caspase-3. IH-901 also caused the down-regulation of FGFR3 mRNA and protein expression and inhibited ERK activity in KMS-11 cells. Our results demonstrate that IH-901 induces apoptosis and inhibits FGFR3 expression and signaling in KMS-11 cells, suggesting candidacy for the chemoprevention and the treatment of myeloma.
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PMID:A novel ginseng saponin metabolite induces apoptosis and down-regulates fibroblast growth factor receptor 3 in myeloma cells. 1296 89

The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.
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PMID:Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. 1502 11

The mechanisms underlying sperm protein 17 (Sp17) gene expression in myeloma cells remained unclear. Using reverse transcription-polymerase chain reaction (RT-PCR), Sp17 transcripts were detected in ARK-B, ARP-1, RPMI-8226 and KMS-11 but not in H929, IM-9, MM1-R and U266 cells. Using a panel of primer pairs in methylation-sensitive PCR to amplify overlapping gene segments, our screening studies showed that the HpaII sites at -359 and -350 are involved in the regulation of Sp17 gene expression. To confirm the differences in methylation status between Sp17-positive and Sp17-negative cell lines, KMS-11 cells (Sp17-positive) and IM-9 cells (Sp17-negative) were subjected to the more accurate method of bisulphite conversion. KMS-11 cells were more hypomethylated at these HpaII sites of exon 1 compared to IM-9 cells, indicating the association of hypomethylated promoter with Sp17 gene expression. In addition, the level of methylation at other CpG sites within the promoter sequence was also higher in IM-9 than KMS-11. Exon 1 was cloned into a reporter vector, pCAT*3 Enhancer. Chloramphenicol acetyl transferase (CAT) activity was restored in cells transfected with the recombinant plasmid, indicating the promoter function of exon 1. Exposure of Sp17-negative cell lines to the hypomethylating agent, 5-azacytidine, resulted in the upregulation of Sp17 gene expression. Our results therefore provide evidence for the regulation of Sp17 gene expression by promoter methylation.
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PMID:Sp17 gene expression in myeloma cells is regulated by promoter methylation. 1538 30


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