Persistence of DNMT3A mutations at long-term remission in adult patients with AML
Gro G Pløen1, Line Nederby, Per Guldberg
1Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.
Abstract:
Mutations in DNMT3A, the gene encoding DNA methyltransferase 3 alpha, have been identified as molecular drivers in acute myeloid leukaemia (AML) with possible implications for minimal residual disease monitoring and prognosis. To further explore the utility of DNMT3A mutations as biomarkers for AML, we developed assays for sensitive detection of recurrent mutations affecting residue R882. Analysis of DNA from 298 diagnostic AML samples revealed DNMT3A mutations in 45 cases (15%), which coincided with mutations in NPM1, FLT3 and IDH1. DNMT3A mutations were stable in 12 of 13 patients presenting with relapse or secondary myelodysplastic syndrome, but were also present in remission samples from 14 patients (at allele frequencies of <1-50%) up to 8 years after initial AML diagnosis, despite the loss of all other molecular AML markers. The mutant DNMT3A allele burden was not related to the clinical course of disease. Cell sorting demonstrated the presence of DNMT3A mutations in leukaemic blasts, but also at lower allele frequencies in T and B-cells from the same patients. Our data are consistent with the recent finding of preleukaemic stem cells in AML, which are resistant to chemotherapy. The persistence of DNMT3A mutations during remission may have important implications for the management of AML.
Insights
Mutations in DNA methyltransferase 3 alpha (DNMT3A) persist in acute myeloid leukaemia (AML) patients during remission, even after other markers disappear. This finding suggests preleukaemic stem cells may explain the persistence and impact AML management.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Mutations in DNMT3A are key drivers in acute myeloid leukemia (AML).
- DNMT3A mutations may serve as biomarkers for minimal residual disease monitoring and prognosis in AML.
- Sensitive assays are needed to detect these mutations.
Purpose of the Study:
- To develop sensitive assays for detecting recurrent DNMT3A mutations at residue R882.
- To investigate the utility of DNMT3A mutations as biomarkers in AML.
- To explore the persistence and implications of DNMT3A mutations during AML remission.
Main Methods:
- Development of sensitive assays for DNMT3A R882 mutations.
- Analysis of DNA from 298 diagnostic AML samples.
- Detection of mutations in diagnostic, relapse, and remission samples using allele frequencies.
- Cell sorting to identify cell types harboring DNMT3A mutations.
Main Results:
- DNMT3A mutations were found in 15% (45/298) of diagnostic AML cases, often co-occurring with NPM1, FLT3, and IDH1 mutations.
- Mutations remained stable in relapsed/secondary AML but were detected in remission samples from 14 patients up to 8 years post-diagnosis, irrespective of other molecular markers.
- DNMT3A mutations were present in leukaemic blasts and, at lower frequencies, in T and B-cells, suggesting presence in preleukaemic stem cells.
Conclusions:
- Persistent DNMT3A mutations during AML remission, potentially in preleukaemic stem cells, have significant implications for AML management.
- The presence of these mutations in remission despite the absence of other molecular markers highlights their stability and potential role in disease recurrence.
- DNMT3A mutations may represent a long-term marker in AML, influencing treatment strategies and monitoring approaches.
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