The prognostic relevance of IDH2 mutations seems to depend upon the affected codons. Indeed, there is growing evidence suggesting that AML carrying IDH2R172 may represent a biologically and clinically distinct entity that is characterized by unique gene- and miRNA-expression

profile, 108 lower CR rate and inferior survival. [108] and [110] The impact of IDH2R140 mutations in CN-AML is more controversial. In fact, Paschka et al. 92 found that IDH2R140 mutations were predictive for inferior outcome in the favorable-risk AZD6738 mouse group of NPM1-mutated/FLT3-ITD–negative AML. In contrast, the HOVON group 96 showed no impact of IDH2 mutations on survival and a recent MRC study found that younger adult AML patients carrying IDH2R140 mutations had a significant better prognosis than those with either IDH2R172 or IDH1 mutations. 110 Human DNA methylation is regulated by the DNA methyltransferase genes DNMT1, DNMT3A and DNMT3B that encode for enzymes that catalyze the transfer of a methyl group onto the 5′-position of cytosine at CpG dinucleotides. 111 DNMT3A and DNMT3B are primarily involved in de novo methylation, 112 whilst DNMT1 acts predominantly as maintenance methyltransferase. [113] and [114] DNA methylation is a key regulator of gene

expression and aberrant CpG island methylation is thought to play an important role in tumorigenesis. Mutations of the DNMT3A gene in AML learn more were independently discovered by three research groups, using next generation sequencing approaches. [15], [115] and [116] They occur in about 20% of AML, are more frequently associated with CN-AML and appear stable during AML evolution. [117] and [118] Their frequency appears lower in patients from Asia, [119] and [120] pointing to an effect of ethnic background. About 95% of DNMT3A mutations occur in the second half of the gene that contains the PDH and methyltransferase domains. R882H is the most prevalent DNMT3A mutation, Liothyronine Sodium accounting for about 80% cases. 121 Both R882H that occurs at the dimer interface of the enzyme and other mutations

that are located at the tetramer interface disrupt tetramerization that is in turn critical for methylation of multiple CpG sites. 122 Mutations of DNMT3B or DNMT3L (the binding partner for DNA methyl-transferases) have not been reported in AML. Unlike mutations of NPM1 that appear specific for AML, 14 those affecting the DNMT3A gene occur in hematological malignancies other than AML, including 2.6-8% of myelodysplastic syndromes [123] and [124] and about 20% of T-cell acute lymphoblastic leukemias. 125 Interestingly, biallelic mutations of DNMT3A occur more frequently in T-ALL than in AML patients. 125 Other characteristics of DNMT3A mutations are shown in Table 1. The mechanism through which DNMT3A mutations contribute to AML remains elusive. Several authors [15] and [126] could not identify a significant correlation between the DNMT3A mutation status, gene expression signature, and DNA methylation patterns. In contrast Yan et al.