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Mutant DNMT3A in acute myeloid leukemia: guilty of inducing genetic instability?

Leukemia volume 27, pages 1777–1778 (2013)Cite this article

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In a recent article in Leukemia, Wakita et al.1 aimed at studying the role of gene mutations in the development of acute myeloid leukemia (AML) relapse and analyzed the mutational landscape in paired samples of 34 patients with de novo AML. Although the authors observed differences in class I and II alterations, mutations in genes regulating DNA methylation did not change between diagnostic and relapse specimens. These findings are of interest, as they support a role of epigenetics-modifying mutations as founder events in the clonal development of AML. Additionally, the authors observed a higher frequency of tandem duplications within the juxtamembrane domain of the Fms-like tyrosine kinase 3 receptor (FLT3-ITD (internal tandem duplications)) at relapse in patients who presented with mutant DNA methyltransferase 3 alpha (DNMT3A) at diagnosis. This led them to assume that mutations in DNMT3A may cause genetic instability and thereby induce FLT3-ITD, ultimately leading to relapse of AML.

We recently described mutations in DNMT3A in 13 of 37 (35%) patients diagnosed with secondary AML (sAML)2 arising from either myelodysplastic syndromes (MDS) or chronic myeloproliferative neoplasias (MPN). In agreement with Wakita et al., the DNMT3A mutations detected at sAML diagnosis were already present at the time of the precedent MDS/MPN in 10 of 10 (100%) cases, suggesting that mutant DNMT3A is a founder event in the development of sAML. FLT3-ITD is a known progression marker from MDS to AML with low frequencies in the MDS and high frequencies in the secondary leukemia samples, respectively.3, 4 We, therefore, asked whether the existence of DNMT3A mutations at MDS/MPN diagnosis might be accountable for the accumulation of FLT3-ITD during the clonal evolution to sAML and reanalyzed all 37 sAML specimens described in Fried et al.2 Screening for mutations in nucleophosmin 1 (NPM1) and the FLT3 tyrosine kinase domain (FLT3-TKD), as well as for the presence of FLT3-ITD was performed as previously described.5, 6 Informed consent was obtained from all individuals and the study was approved by the institutional review board of the Medical University of Graz, Graz, Austria. Statistical correlation of DNMT3A with FLT3-ITD was calculated by Fisher’s exact test using R 2.15.2 (http://www.r-project.org).

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Acknowledgements

This work was supported by Leukämiehilfe Steiermark and the START-Funding-Program of the Medical University of Graz, Graz, Austria (both to AZ).

Author Contributions

AZ was the principal investigator of this study, analyzed the data and wrote the paper. GH and AW performed sequence analyses and analyzed the data. FQ was responsible for statistical analyses. HS contributed AML samples and was involved in data analysis, and in writing of the paper. All authors read and contributed to the final version of the paper.

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Authors and Affiliations

  1. Division of Hematology, Medical University of Graz, Graz, Austria

    A Zebisch, A Wölfler & H Sill

  2. Institute of Pathology, Medical University of Graz, Graz, Austria

    G Hoefler

  3. Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria

    F Quehenberger

Authors
  1. A Zebisch
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  2. G Hoefler
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  3. F Quehenberger
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  4. A Wölfler
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  5. H Sill
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Correspondence to A Zebisch.

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Zebisch, A., Hoefler, G., Quehenberger, F. et al. Mutant DNMT3A in acute myeloid leukemia: guilty of inducing genetic instability?. Leukemia 27, 1777–1778 (2013). https://doi.org/10.1038/leu.2013.48

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