Epigenetic Changesgene Silencing Through Dna Hypermethylation

Expression of genes involved in hematopoiesis may be affected both by gene fusions and point mutations and by epigenetic mechanisms such as DNA methylation. Hypermethylation of cytosine nucleotide residues within CpG-rich regions (CpG islands) in the gene promoters leads to gene inactivation. CpG island hypermethylation has been detected in almost all types of solid tumors and leukemia, but patterns of aberrant DNA methylation appear to differ among particular types of neoplasia, with AML displaying a rela tively high number of methylation targets, some of which are not found in solid tumors.71 There seems to be an overrepresentation of methylated CpG islands on chromosome 11 relative to its size.72

Most studies correlating clinical outcome with methylation of other genes have linked CpG island methylation with poor prognosis. Patients with APL and CDKN2B methylation had a significantly shorter 5-year DFS than those without CDKN2B methylation.73 In another study,74 CDKN2B methylation was frequently detected in therapy-related AML and MDS patients with deletion or loss of 7q and was shown to confer a poor prognosis. More recently, EXT1 hypermethylation, which is more common in APL than in other types of AML, has been reported to increase the likelihood of resistance to treatment with ATRA in a relatively small series of patients.75 Importantly, clinical trials of low-dose hypomethylating agents, such as 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), in AML and MDS have yielded promising results, especially in elderly patients.

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