Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia

• Published in: Blood 2012-06, Vol.119 (24), p.5824-5831
• Main Authors: Ribeiro, Ana Flávia Tibúrcio, Pratcorona, Marta, Erpelinck-Verschueren, Claudia, Rockova, Veronika, Sanders, Mathijs, Abbas, Saman, Figueroa, Maria E., Zeilemaker, Annelieke, Melnick, Ari, Löwenberg, Bob, Valk, Peter J.M., Delwel, Ruud
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Biomarkers, Tumor; Cluster Analysis; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation - genetics; Female; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Multivariate Analysis; Mutant Proteins - metabolism; Mutation - genetics; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Prognosis; Recurrence; Survival Analysis; Treatment Outcome; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-367961

The prevalence, the prognostic effect, and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with acute myeloid leukemia (AML) younger than 60 years. We show mutations in DNMT3A in 96 of 415 patients with newly diagnosed AML (23.1%). Univariate Cox regression analysis showed that patients with DNMT3Amutant AML show significantly worse overall survival (OS; P = .022; hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.04-1.81), and relapse-free survival (RFS; P = .005; HR, 1.52; 95% CI, 1.13-2.05) than DNMT3Awild-type AMLs. In a multivariable analysis, DNMT3A mutations express independent unfavorable prognostic value for OS (P = .003; HR, 1.82; 95% CI, 1.2-2.7) and RFS (P < .001; HR, 2.2; 95% CI, 1.4-3.3). In a composite genotypic subset of cytogenetic intermediate-risk AML without FLT3-ITD and NPM1 mutations, this association is particularly evident (OS: P = .013; HR, 2.09; 95% CI, 1.16-3.77; RFS: P = .001; HR, 2.65; 95% CI, 1.48-4.89). The effect of DNMT3A mutations in human AML remains elusive, because DNMT3Amutant AMLs did not express a methylation or gene expression signature that discriminates them from patients with DNMT3Awild-type AML. We conclude that DNMT3A mutation status is an important factor to consider for risk stratification of patients with AML.