Previous epigenetics research in myelodysplastic syndromes (MDS) mainly focused on the DNA methylation of tumor suppressor genes. Recent studies reported that around 6% of MDS patients have several EZH2 mutations including missense, frameshift and truncated mutations. Histone methyltransferase EZH2 plays a critical role in epigenetic regulation as a bridge between histone methylation/deacetylation and DNA methylation. EZH2 is frequently overexpressed and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with poor survival. Many questions still need further discussion. Moreover, 3-deazaneplanocin can reduce EZH2 levels and H3K27 trimethylation, and synergistic effects are seen in combination with DNA demethylation agents or histone deacetylation inhibitors. All of the above give us more chances to improve epigenetic therapy in MDS. Therefore, the molecular mechanisms of EZH2 in tumorigenesis and the role of EZH2 in MDS are studied.
"EZH2 is located on chromosome 7q, and loss of this chromosome in MDS has long been recognized as a poor prognostic indicator  . Further research has found that it is likely that this poor prognosis in these patients is associated with loss of EZH2   . "
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.
Advances in Hematology 03/2014; 2014(8):103175. DOI:10.1155/2014/103175
[Show abstract][Hide abstract] ABSTRACT: Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology.
Cellular and Molecular Life Sciences CMLS 05/2013; 71(3). DOI:10.1007/s00018-013-1343-z · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dysregulation of cellular epigenetic machinery is considered a major pathogenetic determinant in many malignancies, including myelodysplastic syndromes (MDS). The importance of epigenetic dysfunction in MDS is reflected by the success of hypomethylating agents as standard of care for their treatment. Although these agents improve both survival and quality of life, knowledge gaps remain regarding the precise role of epigenetics in the pathogenesis of MDS and mechanisms by which hypomethylating agents exert their clinical effects. This article reviews the pathogenic role of epigenetic alterations in MDS, including the relationship between genetic and epigenetic abnormalities, and highlights emerging evidence that hypomethylating agents may reprogram the "methylome" while re-establishing hematopoiesis.
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