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Published on: September 20, 2016
Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia
Felicitas Thol1, Frederik Damm, Andrea Lüdeking
1Hannover Medical School, Hannover, Germany.
Purpose:
To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia.
Patients And Methods:
A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1).
Results:
DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients.
Conclusion:
DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
Insights
DNA methyltransferase 3A (DNMT3A) mutations are common in younger acute myeloid leukemia (AML) patients. These mutations are linked to a worse prognosis, impacting overall survival, especially in specific subgroups.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy.
- Identifying genetic markers is crucial for understanding AML prognosis and treatment.
Purpose of the Study:
- To investigate the frequency of DNA methyltransferase 3A (DNMT3A) mutations in AML patients.
- To determine the prognostic significance of DNMT3A mutations in AML.
Main Methods:
- Direct sequencing was used to detect DNMT3A mutations in 489 AML patients.
- Prognostic impact was assessed alongside clinical and genetic risk factors.
Main Results:
- DNMT3A mutations were identified in 17.8% of AML patients under 60.
- Mutations were associated with older age, higher WBC/platelet counts, normal karyotype, and NPM1/FLT3/IDH1 mutations.
- DNMT3A mutations independently predicted shorter overall survival (OS) in the entire cohort and in cytogenetically normal (CN-AML) patients, and lower complete remission (CR) rates in CN-AML.
Conclusions:
- DNMT3A mutations are prevalent in younger AML patients.
- These mutations are associated with an unfavorable prognosis, particularly impacting OS and CR rates in specific AML subtypes.
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