4 1 When Genetics Meets Epigenetics in Cancer Deregulation of th

4.1. When Genetics Meets Epigenetics in Cancer Deregulation of the epigenetic machinery can also occur due to activation or inactivation of the epigenetic regulatory proteins. In other words, the enzymes that maintain and modify the epigenome are themselves frequent targets for mutation and/or

epimutation in neoplasia [27]; for example, DNA methyltransferases themselves have been found to be genetically altered in malignancies, such as DNMT3A [28] and DNMT3B in pancreatic and breast cancer cells [29]. Somatic DNMT3A mutations have been described in approximately 20% of acute myeloid leukemia Inhibitors,research,lifescience,medical (AML) patients, especially in those with an intermediate risk cytogenetic profile and although they did not affect the 5-methylcytosine content [30] they were associated with poor clinical outcome

[30, 31]. How the lack of effect of DNMT3A mutations on 5-methylcytosine content is linked to an otherwise poor clinical outcome is not yet fully understood. It has been suggested that the R882 DNMT3A mutations alter functions of DNMT3A such as its ability to bind other Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical proteins involved in transcriptional regulation and localization to chromatin regions containing methylated DNA [30]. Loss-of-function TET2 mutations were also identified in myeloid neoplasms in 20–30% [32, 33] and have been associated with both good [34] and bad prognoses [35]. Genome sequencing has also revealed the presence of metabolic mutations in patients with myelodysplastic syndromes (MDS) and AML related Inhibitors,research,lifescience,medical to the isocitrate dehydrogenase (IDH) 1 and IDH2 genes [36]. These mutations have been reported in approximately 30% of patients with normal karyotype AML [37, 38] and have been linked to the disruption of various processes such as bone marrow microenvironment changes and impaired differentiation suggesting a proleukemogenic effect. In an AML cohort, IDH1 and IDH2 mutations

were mutually exclusive with TET2 mutations while they shared the similar epigenetic defects with the TET2 mutants. Epigenetic profiling revealed that AML patients with IDH1/2 mutations Inhibitors,research,lifescience,medical displayed global hypermethylation and a specific hypermethylation signature [39]. MLL is another epigenetic modifier that is commonly mutated in acute leukemias and mainly due Mephenoxalone to translocations. In normal karyotype AML cases the incidence of MLL partial tandem duplications (MLL-PTD) is up to 8% whereas in cases of trisomy 11 the incidence reaches 25% [40]. Favorable AMLs such as those with t(8; 21) are MLL-PTD negative [41]. As MLL is a H3K4 methyltransferase, translocations that replace the methyltransferase domain affect its function and have been linked with leukaemic transformation [42]. Mutations affecting the Polycomb repressive LY2157299 supplier complex (PRC) components, such as EZH2, can also affect histone modifications and have recently been reported. EZH2 is the enzymatic component of the PRC2 complex and is a H3K27 methyltransferase.

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