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Low frequency of DNMT3A mutations in pediatric AML, and the identification of the OCI-AML3 cell line as an in vitro model

Leukemia volume 26, pages 371–373 (2012)Cite this article

Recently, next generation sequencing technology has been applied to discover tumor-specific mutations in acute myeloid leukemia (AML) genomes.1 After the finding of recurrent mutations in the enzyme isocitrate dehydroxygenase 1 (IDH1) in AML,2 two studies recently reported the identification of somatic mutations in the DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) gene in adult AML cases.3, 4 Ley et al.3 reported the presence of DNMT3A mutations in 22% of de novo adult AML cases, after the discovery of this mutation by sequencing a whole AML genome. They found that DNMT3A mutations were highly associated with cytogenetically normal (CN)-AML (37% (44 of 120) CN-AML cases). Yan et al.4 detected DNMT3A mutations by sequencing the complete coding region of the genome (exome sequencing) of nine AML-M5 samples. They found that these mutations were restricted to the myelomonocytic (French–American–British (FAB)-M4) and monocytic (FAB-M5) AML subtypes, presenting in 13.6 and 20.5% of these cases, respectively. DNMT3A mutations were localized in the methyltransferase and the plant homeo domain fingers, and impaired DNMT3A methyltransferase activity, or altered histone H3 affinity in vitro. Both studies reported a poor clinical outcome for patients with DNMT3A-mutated AML.3, 4

As data on DNMT3A mutations in pediatric AML were not yet available, we subsequently screened cDNA of a large representative pediatric AML series (n=140; including 34 FAB-M4 and 27 FAB-M5 cases, and including 46 CN-AML cases) from the Dutch Childhood Oncology Group and AML-Berlin Frankfurt Münster Study Group studies for DNMT3A mutations in the region, including amino acids 460–912, in which all but one of the previously reported mutations were found. Remarkably, only two additional cases with DNMT3A mutations were detected; one case harbored a R484W mutation, and the other case harbored a V716F mutation. The characteristics of these cases are presented in Table 1. Of interest, two of the three pediatric cases with DNMT3A mutations concerned an AML of the FAB-M1 subtype, which is in contrast with the (myelo)monocytic morphology predominantly found in adult DNMT3A-mutated AML cases.3, 4 Unlike the poor clinical outcome of adults with DNMT3-mutated AML, all three pediatric cases were in continuous complete remission at last follow-up. In conclusion, the estimated frequency of DNMT3A mutations in our pediatric AML series is only 2.1% (95% confidence interval (CI) 0–4.5%), and 6.4% (95% CI 0–13.4%) in the CN-AML subset. In line with our data, Ho et al.5 recently published that no DNMT3A mutations were observed in their pediatric AML series (n=180). Consistent with this low frequency in children, both adult AML studies reported a high mean age (54.9 and 53.1 years, respectively) for DNMT3A mutants, indicating that these mutations are associated with a disease onset at advanced age.3, 4 Of note, our frequency might be slightly underestimated, as we performed mutational screening on cDNA, and Ley et al.3 showed that 2 out of 21 (10%) mutated alleles were not expressed. However, in the study of Yan et al.,4 all 23 DNMT3A-mutated alleles were expressed.

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Acknowledgements

We acknowledge funding from the Childhood Oncology Foundation Rotterdam, The Netherlands.

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  1. I H I M Hollink, Q Feng and A A Danen-van Oorschot: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands

    I H I M Hollink, A A Danen-van Oorschot, S T C J M Arentsen-Peters, L J Verboon, R Pieters, M M van den Heuvel-Eibrink & C M Zwaan

  2. Department of Cancer Research, Beijing Genomic Institute (BGI), Beijing, China

    Q Feng, P Zhang & J Wang

  3. Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands

    V de Haas

  4. Department of Pediatric Oncology/Hematology, AML-BFM Study Group, Medical School Hannover, Hannover, Germany

    D Reinhardt

  5. AML-BFM Study Group, University Children's Hospital, Münster, Germany

    U Creutzig

  6. Department of Pediatric Oncology/Hematology, Medical School Hannover,

    J Trka

  7. 2nd Medical School, Charles University, Prague, Czech Republic

    J Trka

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Correspondence to C M Zwaan.

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Hollink, I., Feng, Q., Danen-van Oorschot, A. et al. Low frequency of DNMT3A mutations in pediatric AML, and the identification of the OCI-AML3 cell line as an in vitro model. Leukemia 26, 371–373 (2012). https://doi.org/10.1038/leu.2011.210

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