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)

The major histocompatibility complex (MHC) class II transactivator (CIITA) acts as a master switch to activate expression of the genes required for MHC-II antigen presentation. During B-cell to plasma cell differentiation, MHC-II expression is actively silenced, but the mechanism has been unknown. In plasma cell tumors such as multiple myeloma the repression of MHC-II is associated with the loss of CIITA. We have identified that positive regulatory domain I binding factor 1 (PRDI-BF1), a transcriptional repressor, inhibits CIITA expression in multiple myeloma cell lines. Repression of CIITA depends on the DNA binding activity of PRDI-BF1 and its specific binding site in the CIITA promoter. Deletion of a histone deacetylase recruitment domain in PRDI-BF1 does not inhibit repression of CIITA nor does blocking histone deacetylase activity. This is in contrast to PRDI-BF1 repression of the c-myc promoter. Repression of CIITA requires either the N-terminal acidic and conserved PR motif or the proline-rich domain. PRDI-BF1 has been shown to be a key regulator of B-cell and macrophage differentiation. These findings now indicate that PRDI-BF1 has at least two mechanisms of repression whose function is dependent on the nature of the target promoter. Importantly, PRDI-BF1 is defined as the key molecule in silencing CIITA and thus MHC-II in multiple myeloma cells.
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PMID:Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells. 1127 46

DNA methylation has been linked to gene silencing in cancer. Primary effusion lymphoma (PEL) and myeloma are lymphoid malignancies that arise from terminally differentiated B cells. Interestingly, PEL do not express immunoglobulins or most B lineage-specific genes. The B cell-specific B29 (Igbeta/CD79b) gene is silenced in PEL and some myelomas but is expressed in other normal and malignant B cells. B29 expression was reactivated in PEL by demethylating and histone deacetylase inhibiting treatments. Bisulfite sequencing revealed two types of DNA methylation in silenced B29 promoters: at conventional CpG and at CC(A/T)GG B29 promoter sites. The pattern of methylated CpG ((m)CpG) and C(m)C(A/T)GG B29 promoter methylation observed was similar to that recently reported for epigenetic silencing of an integrated retrovirus. Methylation of C(m)C(A/T)GG sites in the B29 promoter significantly repressed in vivo transcriptional activity. Also, methylation of a central conserved C(m)CTGG B29 promoter site blocked the binding of early B cell factor. This methylated motif formed DNA-protein complexes with nuclear extracts from all cell types examined. Therefore, C(m)C(A/T)GG methylation may represent an important type of epigenetic marker on mammalian DNA that impacts transcription by altering DNA-protein complex formation.
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PMID:CmC(A/T)GG DNA methylation in mature B cell lymphoma gene silencing. 1152 27

Pax5 plays a key role in the progression of B cell development. Its expression is observed in a wide range of cell types from early lineage-committed precursors up to mature B cells, but is silenced in terminal differentiated plasma cells. In this report, we show that DNA methylation is involved in the silencing of Pax5. In the Pax5-expressing cell lines 38B9 (pre-B) and 2PK-3 (mature B), all CpG sites in TATA-containing upstream promoter were unmethylated, whereas these sites were completely methylated in myeloma cell lines FO and Sp-2/0, which do not express Pax5. Demethylation of FO and Sp-2/0 with 5-aza-2'-deoxycytidine (5-aza-dC) resulted in Pax5 re-expression with the concomitant expression of CD19 and mb-1 genes, which are known to be the target genes of Pax5. Re-expression of Pax5 was also induced by trichostatin A (TSA), which was a specific inhibitor of histone deacetylase. This re-expression was, however, transcribed only from the TATA-less downstream promoter. Taken together, we concluded that the upstream promoter was predominantly inactivated by DNA methylation, while the downstream promoter was repressed by the histone deacetylation. This synergetic inactivation of two promoters results in the final silencing of Pax5 expression in terminally differentiated B cell lines.
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PMID:DNA methylation dominates transcriptional silencing of Pax5 in terminally differentiated B cell lines. 1204 82

Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.
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PMID:Molecular sequelae of histone deacetylase inhibition in human malignant B cells. 1253 99

Waldenstrom's macroglobulinemia (WM) remains an incurable B-cell malignancy, necessitating urgent development of novel treatment strategies. Building on our experience on bed-to-bedside translational studies for multiple myeloma (mm), we identified a constellation of novel classes of anti-WM agents, including the proteasome inhibitor PS-341; the ansamycin family of inhibitors (eg, geldanamycin and its analogues) of the heat-shock protein 90 (hsp90) molecular chaperone; histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA); and the thiazolidinedione group of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (eg, ciglitazone or rosiglitazone). Our preclinical data show that these classes of agents induce growth arrest and apoptosis of WM cells, at concentrations relevant to those achieved in previous clinical uses of these drugs, and suggest that novel therapeutic strategies for WM can be designed to include combinations of these agents, to simultaneously target multiple levels of diverse pathways important for tumor cell growth and survival, and thus maximize the pro-apoptotic activities of these agents and/or neutralize protective responses of WM against their effects. These molecular studies provide a framework for rational design of the next generation of combination therapies for WM.
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PMID:Novel biologically based therapies for Waldenstrom's macroglobulinemia. 1272 Jan 59

Multiple myeloma (MM), a hematologic malignancy, remains fatal despite all available therapies. Initial treatment with conventional drugs effectively induces MM cell death/apoptosis; however, prolonged drug exposures results in the development of de novo chemoresistance. Because MM is a bone marrow (BM) cancer, the progression of disease and drug efficacy is highly influenced by the BM microenvironment. Novel agents, such as proteasome inhibitors (PS-341), 2-methoxyestradiol (2ME2), thalidomide and its immunomodulatory derivatives (IMiDs), and histone deacetylase (HDAC) inhibitors target the MM cell in its BM microenvironment; thereby enhancing anti-MM activity as well as preventing development of drug-resistance. The transcriptional events and signaling pathways, which mediate these responses in MM cells are now being delineated, and may serve to identify novel therapeutic targets based upon interrupting MM cell growth or triggering MM cell death.
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PMID:Mechanisms of cell death and survival in multiple myeloma (MM): Therapeutic implications. 1281 76

There has been considerable debate about the relationship between epilepsy and cancer, in particular whether the incidence of cancer is increased in people with epilepsy and whether antiepileptic drugs promote or protect against cancer. We review available evidence from animal experiments, genotoxicity studies and clinico-epidemiological observations, and discuss proposed mechanisms underlying the association between epilepsy and cancer. A carcinoma-promoting effect has been seen unequivocally in rodent models for phenobarbital and phenytoin; phenobarbital promoted liver tumours and phenytoin caused lymphoid cell and liver tumours in rats. Early human epidemiological studies found an association between phenobarbital and hepatocellular carcinoma, and several subsequent studies suggested an association with lung cancer. An association with brain tumours has also been demonstrated. Phenytoin has been causally implicated in three human cancers: lymphoma, myeloma and neuroblastoma, the latter specifically in the setting of foetal hydantoin syndrome. However, despite considerable long-term pharmaco-epidemiological data being available for both antiepileptic drugs, evidence for human carcinogenicity is not consistent and both are considered only possibly carcinogenic to humans. Valproate, however, has been found to exert an antiproliferative effect on certain cancer cell lines both in vitro and in vivo. A corresponding cancer-suppressive effect has not been studied in human epidemiological studies, though there are now preliminary reports of the use of valproate in human haematological and solid tumours. The anticancer activity of valproate appears to be driven by histone deacetylase inhibition and to be independent of hormone or multidrug protein resistance dependent mechanisms. The newer antiepileptic drugs appear to be safe, as no carcinogenicity has been demonstrated either during regulatory testing or in post-marketing surveillance. Nevertheless, the subject of cancers and epilepsy constitutes a promising agenda for clinical and experimental research in the future.
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PMID:Cancer risk in people with epilepsy: the role of antiepileptic drugs. 1557 65

DNA methylation is involved in malignancy and is seen, in progression, in more than 80% of all solid tumours. Methylation is one of the main physiological processes to induce silencing of gene expression. Much work has focused on the suppressor gene p16, which acts as a negative cell cycle regulator, while its inhibition (via methylation) will have a positive effect on the cell cycle advance. The methylation status of the p16 gene was analysed in a group of 159 patients. Methylation of the p16 gene was seen in 41/98 (42%) patients with multiple myeloma and 4/5 (80%) patients with primary plasma cell leukaemias. This data favours the importance of p16 methylation on cell cycle regulation in multiple myeloma. In a proposed mechanism, methylated CpG islands attract a protein, MeCP2, which recruits a transcriptional inhibitory complex that includes histone deacetylases. The deacetylated lysine tails of the histones closely interact with DNA, resulting in a transcriptionally repressed chromatin with inhibited gene transcription, providing potential synergy between demethylating drugs and histone deacetylase inhibitors. Based on the knowledge of epigenetic mechanisms, the potential application of demethylating agents should be further investigated. Multiple myeloma remains an incurable disease, so new treatment strategies are needed to improve the outcome of patients.
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PMID:Analysis of methylation pattern in multiple myeloma. 1616 69

The aim of this study was to evaluate the effects of valproic acid (VPA), as a histone deacetylase inhibitor, on myeloma cell lines and on sorted human bone marrow multiple myeloma cells. VPA induced accumulation of acetylated histones, potently inhibited proliferation in a dose-dependent manner and induced apoptosis in all myeloma cell lines tested as well as in sorted primary multiple myeloma cells. Cell cycle analysis indicated an arrest in G0/1 phase in response to VPA. Accumulation of p21 and reduced levels of cyclin D1 were detected. The production of vascular endothelial growth factor was significantly inhibited by VPA. These results provide the framework for clinical trials.
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PMID:The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma. 1646 12

Conventional intravenous chemotherapy regimens are toxic, cumbersome, and negatively affect patients' quality of life, with oral treatment preferable to most patients with cancer. Multiple myeloma is the second most common haematological malignant disease, but cannot be cured with conventional and high-dose chemotherapy. New oral treatments that target myeloma cells or bone marrow are being developed that are highly effective yet have low toxic effects, such as the immunomodulatory drugs thalidomide and lenalidomide. Several treatments in early development have shown antimyeloma activity, including: CHIR-258, which inhibits fibroblast growth factor receptor 3; NVP-ADW742, which inhibits insulin-like growth factor receptor 1; and PTK787, which inhibits vascular endothelial growth factor. Additional drugs aimed at switching off silenced genes include histone deacetylase inhibitors. The availability of these various oral treatments is hoped to improve regimens that, if used sequentially or in combination, offer the potential of making multiple myeloma a chronic disease, thereby extending patients' lifespans and improving quality of life.
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PMID:Advances in oral therapy for multiple myeloma. 1657 47


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