areti regkli

Abstract: Multiple Myeloma (MM) is a malignant hematological disease that is characterized by clonal expansion of malignant plasma cells/plasmablasts in the bone marrow (BM). MM is a very heterogenous disease, and MM cells are dependent on the BM microenvironment for survival, growth, and diferetiation1. A few partner genes have been identified as primary, nonrandom translocation partners2.Multiple genetic aberrations are observed during the pathogenesis of MM3.Two major interactive epigenetic modifications that result in a changed transcriptional activity are: (a) DNA methylation of cytosine bases within a CpG dinucleotide and (b) posttranscriptional histone modifications To what extent epigenetic changes occur in MM is not known. For a few genes, e.g., cell cycle regulators p15INK4B and p16INK4A, death-associated protein kinase, suppressor of cytokine signaling 1, and genes in the Wnt pathway, promoter hypermethylation has been shown to occur in 20% to 40% of MM patients4-7. However, a comprenhesive picture of the aberrant methylation in MM, and an understanding of how DNA methylation may contribute to the pathogenesis of MM are still lacking. In MM, hypermethylation of genes including p15,p16, DAP-kinase, BAD, BAK, BAX, BIK, SOCS-1, and E-Cadherin, has been reported 8-13. Moreover, the growth factor interleikin-6 has been implicated in processes regulating epigenetic gene silencing in MM14. Furthermore, histone deacetylase inhibitors (HDACi) have been shown to decrease survival of human MM cells in vitro by affecting genes involved in cell cycle and cell death pathways and by potentiating other proapoptotic agents 15-18. 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.