We examined 79 acute myeloid leukemia (AML) patients for DNA methylation of 12 tumor suppressor genes (TSG) and 24 homeobox domain (Hox) genes, and additionally for mutations in DNMT3A gene.
Patients with persistent DNMT3A R882 who cleared all other AML mutations and did not acquire new mutations (n = 30), trended towards longer disease-free survival (1·6 vs. 0·6 years, P = 0·06) than patients with persistence of DNMT3A R882, in addition to other mutations or acquisition of new AML-associated mutations, such as those in TET2, JAK2, ASXL1 and TP53 (n = 12).
This report represents the first documentation of the same variant (DNMT3Ap.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML.
Our data indicate that DNMT3A gene is mutated mainly in AML, but it occurs in other cancers, such as ALL and lung cancer, despite the lower incidences.
Aberrant hypomethylation of DNMT3A gene was found in 55.3% (84/152) of AML cases, but the status of DNMT3A hypomethylation was not correlated with the expression of four DNMT3A isoforms as well as DNMT3A mutation.
Patients with acute myeloid leukemia (AML) frequently harbor mutations in genes involved in the DNA (hydroxy)methylation pathway (DNMT3A, TET2, IDH1, and IDH2).
To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM)(+/-) hematopoietic stem/progenitor cells cotransduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD), which often occur simultaneously in human AML patients.
Also, direct mutations in the epigenetic master regulators EZH2 and DNMT3A were recently identified in AML and in diseases leading to secondary leukemia.
Many of these mutations mapped to DNMT3A regions known to interact with proteins that themselves contribute to AML, such as thymine DNA glycosylase (TDG).
In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type.
We demonstrate that aberrant hypermethylation within the gene DNA methyltransferase 3A (DNMT3A) - which may contribute to initiation of acute myeloid leukemia (AML) - is particularly observed in AML samples that reveal significantly more age-associated DNAm changes.
Our results provided novel insight into the role of the DNMT3AR882H mutation in AML pathogenesis and suggested that targeting the cellular GSH synthetic pathway could enhance the current therapy for AML patients with the DNMT3AR882H mutation.