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DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid
V I Gaidzik1, D Weber1, P Paschka1
1Universitätsklinikum Ulm, Ulm, Germany.
Abstract:
We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia patients harboring DNA methyltransferase 3A-R882H/-R882C mutations (DNMT3Amut). MRD was determined by real-time quantitative PCR (RQ-PCR) in 1494 samples of 181 DNMT3Amut patients. At the time of diagnosis, DNMT3Amut transcript levels did not correlate with presenting clinical characteristics and concurrent gene mutations as well as the survival end points. In Cox regression analyses, bone marrow (BM) DNMT3Amut transcript levels (log10-transformed continuous variable) were not associated with the rate of relapse or death. DNMT3Amut transcript levels were significantly higher in BM than in blood after induction I (P=0.01), induction II (P=0.05), consolidation I (P=0.004) and consolidation II (P=0.008). With regard to the clinically relevant MRD time points, after two cycles of induction and at the end of therapy, DNMT3Amut transcript levels had no impact on the end point remission duration and overall survival. Of note, only a minority of the patients achieved RQ-PCR negativity, whereas most had constantly high DNMT3Amut transcript levels, a finding which is consistent with the persistence of clonal hematopoiesis in hematological remission.
Insights
Minimal residual disease (MRD) monitoring using DNA methyltransferase 3A mutations (DNMT3Amut) did not predict outcomes in acute myeloid leukemia. High DNMT3Amut transcript levels persisted, indicating ongoing clonal hematopoiesis despite remission.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Minimal residual disease (MRD) monitoring is crucial for predicting outcomes in acute myeloid leukemia (AML).
- Specific mutations, like DNA methyltransferase 3A-R882H/-R882C (DNMT3Amut), are found in a subset of AML patients.
- The prognostic value of MRD monitoring in DNMT3Amut-harboring AML requires further investigation.
Purpose of the Study:
- To investigate the prognostic impact of MRD monitoring in AML patients with DNMT3A mutations.
- To assess the correlation between DNMT3Amut transcript levels and clinical characteristics, gene mutations, and survival endpoints.
- To evaluate the utility of MRD monitoring for predicting relapse and survival in this specific AML subgroup.
Main Methods:
- Real-time quantitative PCR (RQ-PCR) was used to determine MRD levels.
- 1494 samples from 181 DNMT3Amut AML patients were analyzed.
- Cox regression analyses were performed to assess associations with relapse and survival.
Main Results:
- DNMT3Amut transcript levels at diagnosis did not correlate with clinical features or survival.
- Bone marrow DNMT3Amut transcript levels were consistently higher than in peripheral blood post-induction and consolidation therapies.
- DNMT3Amut transcript levels at key MRD time points did not impact remission duration or overall survival.
Conclusions:
- MRD monitoring of DNMT3Amut transcript levels has no prognostic impact in AML patients.
- Persistent high DNMT3Amut transcript levels suggest ongoing clonal hematopoiesis even in hematological remission.
- These findings highlight the limitations of current MRD monitoring strategies for DNMT3Amut AML.
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