Rare mutations in DNMT3A in myeloproliferative neoplasms and myelodysplastic syndromes

Abstract

Alterations of epigenetic marks are thought to play an important role in myeloid malignancies. In particular, aberrant DNA methylation is a hallmark of these diseases. DNMT3A and DNMT3B methyltransferases have predominant role in de novo methylation of DNA. Mutations in DNMT3A have been found in roughly 20% of acute myeloid leukemia (AML). 1 , 2 , 3 The precise mechanism by which DNMT3A may affect DNA methylation is not known. The TET2 gene encodes an enzyme that favors the transformation of 5-methylcytosines in 5-hydroxymethylcytosines. TET2 function requires alpha-ketoglutarate (αKG). TET2 is frequently mutated in myeloid diseases. Mutation in IDH1 and IDH2 changes their enzymatic activity and induces an hypermethylation of AML DNA. 3 Mutated IDH1/2 enzymes catalyze αKG into 2-hydroxyglutarate (2HG). Production of 2HG impairs TET2 function. This explains why mutations in TET2 and in IDH1/2 are mutually exclusive. 4 In contrast, mutations in IDH1/2 are more frequent in AML cases with DNMT3A mutations. 2