Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3A(R882) mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A(R882) mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3A(R882) mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A(R882) mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A(R882) mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3A(R882)/FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3A(R882) mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A(R882) mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Automated summary

Nucleophosmin1 (NPM1) mutations are common in acute myeloid leukemia (AML) and have been considered as a favorable prognostic factor. However, our analysis of 605 Japanese AML patients, including 174 with NPM1-mutated AML, showed that NPM1 mutations were not associated with better overall survival (OS). Instead, mutations in the DNMT3A gene (DNMT3A(R882) mutations) were found to be a strong predictor of poor prognosis in all AML cases and NPM1-mutated AML cases. The presence of DNMT3A(R882) mutations, as well as the co-occurrence of FLT3-ITD, NPM1, and DNMT3A(R882) mutations (triple mutations), were independent factors associated with worse OS.