Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factor receptor 3 (FGFR3) protein is aberrantly expressed in approximately 15% of cases of plasma cell myeloma as a result of t(4;14)(p16.3;q32), and FGFR3 expression in myeloma is associated with an adverse prognosis. Novel, recently developed therapeutic agents that target the FGFR3 pathway are currently in clinical trials for myeloma. Although extensively studied in plasma cell neoplasms, there is little information in the literature regarding FGFR3 expression in malignant lymphomas, and it is unclear whether lymphoma patients may also benefit from anti-FGFR3 therapy. We, therefore, examined the expression of FGFR3 by immunohistochemistry in 70 cases of malignant lymphoma using tissue microarrays and whole paraffin sections. Of 22 cases of plasma cell myeloma analyzed as controls, FGFR3 positivity was seen in 3/5 t(4;14) positive cases (60%) and in none of 17 t(4;14) negative cases (P=0.006). Weak-to-moderate cytoplasmic FGFR3 staining was seen in 6/43 (12%) B-cell non-Hodgkin lymphomas and 2/17 (12%) T-cell lymphomas, with staining observed at low incidence in many histologic types. Cytoplasmic staining was also seen infrequently in classic Hodgkin lymphoma (1/10, 10%). Membrane staining was not observed in any case of malignant lymphoma. These results indicate that aberrant FGFR3 staining may be seen infrequently in many forms of malignant lymphoma, although dysregulation of this pathway does not seem to contribute to lymphomagenesis in the majority of cases. Moreover, these findings suggest at least most patients with malignant lymphomas are unlikely to benefit from novel agents targeting the FGFR3 pathway.
 ...
PMID:Fibroblast growth factor receptor 3 (FGFR3) expression in malignant lymphomas. 1852 86

Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic agents. Our laboratory has recently reported that phenylhexyl isothiocyanate (PHI), a synthetic isothiocyanate, is an inhibitor of HDAC. In this study we examined whether PHI is a hypomethylating agent and its effects on myeloma cells. RPMI8226, a myeloma cell line, was treated with PHI. PHI inhibited the proliferation of the myeloma cells and induced apoptosis in a concentration as low as 0.5 muM. Cell proliferation was reduced to 50% of control with PHI concentration of 0.5 muM. Cell cycle analysis revealed that PHI caused G1-phase arrest of RPMI8226 cells. PHI induced p16 hypomethylation in a concentration- dependent manner. PHI was further shown to induce histone H3 hyperacetylation in a concentration-dependent manner. It was also demonstrated that PHI inhibited IL-6 receptor expression and VEGF production in the RPMI8226 cells, and reactivated p21 expression. It was found that PHI induced apoptosis through disruption of mitochondrial membrane potential. For the first time we show that PHI can induce both p16 hypomethylation and histone H3 hyperacetylation. We conclude that PHI has dual epigenetic effects on p16 hypomethylation and histone hyperacetylation in myeloma cells and targets several critical processes of myeloma proliferation.
 ...
PMID:Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways. 1857 63

This study was purposed to investigate whether phenylhexyl isothiocyanate (PHI) can reduce p16 gene methylation level or not. The myeloma U226 cell line was cultured with PHI of 0, 5, 10 micromol/L for 72 hours, then DNA was extracted. Hydrosulfite was used to treat the genome DNA of healthy adult, PCR amplification was carried out by using this DNA as template. The gene chip detecting methylation changes of 3 CpG in promoter region of p16 gene was constructed by designing a pair of probes which contain one methylated and one unmethylated probes. This pair of probes was used to detect 3 consecutive sites of CpG island in p16 gene. The standard curve was constructed by using gene chip after the methylated and unmethylated DNA were mixed at different ratio. Then treated samples of U266 cells were dotted on gene chip, obtained results were compared with standard curve to get the quantitative results. The results indicated that the probes on chip had excellent reproducible ability and precision, the methylation level of p16 gene in U266 cells treated with 0, 5 and 10 micromol/L of PHI was determined as 78.2%, 61.7% and 54.8%, respectively. It is concluded that the PHI can reduce the methylation level of p16 gene in U266 cells.
 ...
PMID:[Phenylhexyl isothiocyanate reducing U266 cell line methylation level of p16 gene]. 1892 95

We established a myeloma cell line (RPMI8226) with cyclin D1 overexpression in which the transfected cyclin D1 gene was stably expressed. D1 transfectants showed down-regulation of cyclin D2. Cell proliferation analysis did not show any differences among RPMI8226, mock control, and D1 transfectants. The number of S-phase cells increased while the number of G0/G1- and G2/M-phase cells decreased in D1 transfectants, which indicates a prolonged S-phase caused by cyclin D1 transfection. A decreased number of G2/M-phase cells was also detected in myeloma cells of patients with translocation t(11;14)(q13;q32). Western blot analysis revealed an increase in the hyperphosphorylated form of retinoblastoma (Rb) protein in D1 transfectants; however, the expression of p53, p16, Bax, Bad, Bcl-2, and Mcl-1 did not significantly change. Treatment with anti-myeloma drugs (melphalan, dexamethasone, bortezomib and immunomodulatory compounds) induced apoptosis earlier in D1 transfectants compared with RPMI8226 and mock control via the activation of both caspase-8 and -9. However, we could not detect a relationship between cyclin D1 expression and the response to treatment with VAD and bortezomib. Therefore, we assume that high sensitivity to anti-myeloma drugs depends on the duration of the S-phase, but a clinical response might depend on the number of myeloma cells with cyclin D1 overexpression.
 ...
PMID:Ectopic cyclin D1 overexpression increases chemosensitivity but not cell proliferation in multiple myeloma. 1902 Jul 53

MMSET is expressed ubiquitously in early development and its deletion is associated with the malformation syndrome called Wolf-Hirschhorn syndrome. It is involved in the t(4;14) (p16;q32) chromosomal translocation, which is the second most common translocation in multiple myeloma (MM) and is associated with the worst prognosis. MMSET expression has been shown to promote cellular adhesion, clonogenic growth and tumorigenicity in multiple myeloma. MMSET expression has been recently shown to increase with ascending tumor proliferation activity in glioblastoma multiforme. These data demonstrate that MMSET could be implicated in tumor emergence and/or progression. Therefore, we compared the expression of MMSET in 40 human tumor types--brain, epithelial, lymphoid--to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. We found significant overexpression of MMSET in 15 cancers compared to their normal counterparts. Furthermore MMSET is associated with tumor aggressiveness or prognosis in many types of these aforementioned cancers. Taken together, these data suggest that MMSET potentially acts as a pathogenic agent in many cancers. The identification of the targets of MMSET and their role in cell growth and survival will be key to understand how MMSET is associated with tumor development.
 ...
PMID:MMSET is overexpressed in cancers: link with tumor aggressiveness. 1912 Dec 87

We report a 68-year-old Korean man presenting with asymptomatic erythematous polycyclic annular firm plaques on his back that spread to the right shoulder. Histopathologic examination showed dense, diffuse infiltrates involving the entire dermis, consisting of atypical lymphocytes with many centrocytes and a few centroblasts. Spindle-shaped cells with elongated, twisted nuclei containing dispersed chromatin were also seen. Immunohistochemical analysis showed that all of the cells were strongly positive for CD20, CD21, CD79a and CD45, while they were negative for CD3, CD5, CD10, CD23, CD35, CD43, CD45RO and CD68. The spindle cells were also negative for smooth-muscle actin, desmin, S-100 and CD34. They consistently expressed nuclear bcl-6, but did not express bcl-2, multiple myeloma-1 and p16. We diagnosed him with primary cutaneous spindle cell B-cell lymphoma (PCSBCL) and treated him with six cycles of cyclophosphamide, adriamycin, vincristine, prednisone and rituximab (R-CHOP) chemotherapy; his skin lesions disappeared completely. Immunohistochemical profiles suggest that PCSBCL is a variant of primary cutaneous follicle center lymphoma.
 ...
PMID:Primary cutaneous spindle cell B-cell lymphoma with multiple figurate erythema-like manifestation. 1912 34

Dysregulation of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) plays a pathogenic role in a number of human hematopoietic malignancies and solid tumors. These include t(4;14) multiple myeloma associated with ectopic expression of FGFR3 and t(4;12)(p16;p13) acute myeloid leukemia associated with expression of a constitutively activated fusion tyrosine kinase, TEL-FGFR3. We recently reported that FGFR3 directly tyrosine phosphorylates RSK2 at Y529, which consequently regulates RSK2 activation. Here we identified Y707 as an additional tyrosine in RSK2 that is phosphorylated by FGFR3. Phosphorylation at Y707 contributes to RSK2 activation, through a putative disruption of the autoinhibitory alphaL-helix on the C terminus of RSK2, unlike Y529 phosphorylation, which facilitates ERK binding. Moreover, we found that FGFR3 interacts with RSK2 through residue W332 in the linker region of RSK2 and that this association is required for FGFR3-dependent phosphorylation of RSK2 at Y529 and Y707, as well as the subsequent RSK2 activation. Furthermore, in a murine bone marrow transplant assay, genetic deficiency in RSK2 resulted in a significantly delayed and attenuated myeloproliferative syndrome induced by TEL-FGFR3 as compared with wild-type cells, suggesting a critical role of RSK2 in FGFR3-induced hematopoietic transformation. Our current and previous findings represent a paradigm for tyrosine phosphorylation-dependent regulation of serine-threonine kinases.
 ...
PMID:Fibroblast growth factor receptor 3 associates with and tyrosine phosphorylates p90 RSK2, leading to RSK2 activation that mediates hematopoietic transformation. 1922 61

Multiple myeloma (MM) is a B-cell neoplasia characterized by the clonal proliferation of plasma cells. Besides known genetic abnormalities, epigenetic changes are also known to effect MM pathogenesis. DNA methylation is an epigenetic mechanism that silences genes by adding methyl groups to cytosine-guanine dinucleotides at the promoter regions. In this study, the methylation status of four genes; p16, O6-methyl guanine DNA methyl transferase (MGMT), death-associated protein kinase (DAPK) and E-cadherin (ECAD); at the time of diagnosis was investigated using methylation-specific polymerase chain reaction (MS-PCR). In the 20 cases studied; methylation of the promoter regions of p16, MGMT, DAPK and ECAD genes was detected in 10%, 40%, 10% and 45% of the cases, respectively. In 65% (13/20) of cases, at least one of the genes studied had promoter methylation; while 35% of cases (7/20) had methylated promoters of more than one gene. There was a significant correlation between promoter hypermethylation of MGMT and the presence of extramedullary involvement; but for the other genes no correlation was found regarding disease properties like age, disease stage, clinical course and the presence of lytic bone lesions. Determining the methylation profiles of genes in MM, could lead to a new understanding of the disease pathogenesis and guide the assessment of treatment options.
 ...
PMID:Detecting methylation patterns of p16, MGMT, DAPK and E-cadherin genes in multiple myeloma patients. 1930 4

We report serial genetic studies on a young female patient initially diagnosed with asymptomatic smouldering myeloma who progressed to symptomatic myeloma 4.5 years after presentation. An unbalanced translocation, der(14)t(4;14)(p16;q32), was initially found in all plasma cells plus deletions of other chromosomal regions as detected by array-based comparative genomic hybridization. Deletion of chromosome 13 was observed in a minor population of plasma cells (<20%) for the first two years, increasing to 100% of plasma cells by the time of multiple myeloma diagnosis. Loss of 1p and a rearrangement of MYC were first observed in a small population of plasma cells one year prior to the clinical diagnosis of multiple myeloma, but these subclones increased rapidly in size to become the major population suggesting that they were directly involved in the transformation process. This case report provides a unique insight into the mechanisms of disease progression from smouldering multiple myeloma to multiple myeloma.
 ...
PMID:Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case. 1945 99

Aberrant DNA methylation is considered an important epigenetic mechanism for gene inactivation. Monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma (MM). We have analyzed methylation status of p15 INK4B , p16 INK4A , ARF, SOCS-1, p27 KIP1 , RASSF1A, and TP73 genes in bone marrow DNA samples from 21 MGUS and 44 MM patients, in order to determine the role of aberrant promoter methylation as one of the steps involved in the progression of MGUS to MM. Methylation specific polymerase chain reaction assay followed by DNA sequencing of the resulting product was performed. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS (14%; p=0,006). Methylation frequencies of TP73, ARF, p15 INK4B , p16 INK4A , and RASSF1A were comparable in MGUS: 33%, 29%, 29%, 5%, and 0%, to that observed in MM: 45%, 29%, 32%, 7%, and 2%. All patients lacked methylation at p27 KIP1 gene. In both entities, a concurrent methylation of p15 INK4B and TP73 was observed. The mean methylation index of MGUS was lower (0.16) than that of MM (0.24; p<0.05). Correlations with clinicopathologic characteristics showed a higher mean age in MGUS patients with SOCS-1 methylated (p<0.001); meanwhile in MM, methylation of p15 INK4B was more frequent in males (p=0.009) and IgG isotype (p=0.038). Our findings suggest methylation of TP73, ARF, p15 INK4B , and p16 INK4A as early events in the pathogenesis and development of plasma cell disorders; meanwhile, SOCS-1 methylation would be an important step in the clonal evolution from MGUS to MM.
 ...
PMID:DNA methylation analysis of tumor suppressor genes in monoclonal gammopathy of undetermined significance. 1972 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>