Recurrent DNMT3A mutations in patients with myelodysplastic syndromes

Abstract

Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.

Figure 1. Location of mutations in the DNMT3A gene

The positions and predicted translational consequences of DNMT3A mutations detected in 150 MDS samples are shown. Each circle is a mutation found in one patient. One patient has two mutations in DNMT3A. The conserved proline-tryptophan-tryptophan-proline (PWWP), zinc finger (ZNF), and methyltransferase (MTase) domains are shown. *, stop codon.

Figure 2. Survival analysis of MDS patients with DNMT3A mutations

(A) the overall survival of MDS patients with DNMT3A mutations compared to MDS patients without DNMT3A mutations. (B) the event-free survival of MDS patients with or without DNMT3A mutations. (C) progression to AML in MDS patients with or without DNMT3A mutations.