DNMT3A R882 mutations in patients with cytogenetically normal acute myeloid leukemia and myelodysplastic syndrome

Abstract

Several molecular markers have been described that help to classify patients with acute myeloid leukemia (AML), a heterogeneous hematopoietic tissue neoplasm, into risk groups. We determined the frequency of DNMT3A mutations, their associations with clinical and molecular characteristics and outcome, in primary, cytogenetically-normal AML (CN-AML) and CN-myelodysplastic syndrome (MDS). A total of 63 CN-AML and 16 CN-MDS patients were analyzed for mutations in DNMT3A, codon R822 by direct sequencing and mutation of NPM1 and FLT3/ITD. DNMT3A mutations were found in 17/63 (27%) of CN-AML and in 1/16 (6.3%) of CN-MDS patients. Patients with DNMT3A mutations were older (p=0.047), had higher white blood cell (WBC) counts (p=0.046), more often belonged to FAB groups M4 and M5 (p=0.017), and were more associated with NPM1 mutations (p=0.017), than those with wild-type DNMT3A. DNMT3A-mutated patients had shorter overall disease survival (p<0.001) and disease-free survival (p=0.014) when the entire patient cohort was considered, which remained significant in multivariate analysis. We conclude that DNMT3A R882 mutations are recurrent molecular aberrations in CN-AML, less frequent in CN-MDS, and that testing for R882 mutations may provide a useful tool for refining risk classification of CN-AML.

Keywords: Acute myeloid leukemia; DNMT3A; Leukemogenesis; Myelodysplastic syndrome; Oncogenes.