Analysis of methylation pattern in multiple myeloma.
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.
San-Miguel
Jesús
J
Servicio de Hematología, Hospital Universitario de Salamanca, Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain. sanmigiz@usal.es
García-Sanz
Ramón
R
López-Pérez
Ricardo
R
D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
D002868:Chromosomal Proteins, Non-Histone; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; D006655:Histone Deacetylases