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Acute myeloid leukemia

DNMT3A mutations are over-represented in young adults with NPM1 mutated AML and prompt a distinct co-mutational pattern

Leukemia volume 33, pages 2741–2746 (2019)Cite this article

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Acute myeloid leukaemia (AML) is a disease of the elderly, with an increasing incidence over lifetime [1]. The occurrence of age-related clonal hematopoiesis (ARCH), is one of the main causes of AML development [1], but is not sufficient for malignant transformation, and further oncogenic hits in driver genes are required for AML onset. The most frequent age-related mutations are found in DNMT3A [2]. NPM1 disruption occurs more frequently in young AML patients (≤60 years) [3], whereas other hits, such as mutations in spliceosome genes SF3B1 and SRSF2, are almost exclusively found in elderly patients, suggesting a different disease biology [4]. Mutant DNMT3A was shown to be the most frequent co-mutation in NPM1-positive AML [5], which is counterintuitive given its known increase with age. In this study, we dissect the age association of known co-mutations in NPM1mut AML compared to NPM1 wild type (NPM1wt) AML in a large cohort of patients.

This is a retrospective report on 9010 patients with de novo AML diagnosed at our institution by cytomorphology, immunophenotyping and genetic studies according to WHO criteria from 2005 to 2018 (Table S1). Molecular mutation screening for genes recurrently mutated in AML was performed (supplemental methods).

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Acknowledgements

We thank all patients and clinicians for their participation in this study and all co-workers in our laboratory for their excellent technical assistance.

Author contributions

AH and CH designed the study. LVC and AH interpreted the data and wrote the manuscript. MM, SJ and FD did molecular analyses. SH helped with statistical analysis. TH was responsible for cytomorphologic analyses, CH for cytogenetic and FISH analyses and WK for immunophenotyping. All authors read and contributed to the final version of the manuscript.

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Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Munich, Germany

    Luca Vincenzo Cappelli, Manja Meggendorfer, Frank Dicker, Sabine Jeromin, Stephan Hutter, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach & Alexander Höllein

  2. Department of Precision and Translational Medicine, Sapienza University, Rome, Italy

    Luca Vincenzo Cappelli

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  1. Luca Vincenzo Cappelli
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Correspondence to Alexander Höllein.

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Conflict of interest

AH, MM, FD, SJ, SH: Employment by MLL Munich Leukemia Laboratory; LVC: grant by Torsten Haferlach Leukämiediagnostikstiftung. CH, WK, TH: Equity ownership of MLL Munich Leukemia Laboratory.

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Part of this work was presented at the 60th annual meeting of the American Society of Hematology, San Diego, CA, December 2018 (abstract #0996).

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Cappelli, L., Meggendorfer, M., Dicker, F. et al. DNMT3A mutations are over-represented in young adults with NPM1 mutated AML and prompt a distinct co-mutational pattern. Leukemia 33, 2741–2746 (2019). https://doi.org/10.1038/s41375-019-0502-0

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