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Landmark analysis of DNMT3A mutations in hematological malignancies

Leukemia volume 27, pages 1573–1578 (2013)Cite this article

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Methylation of CpG islands is an epigenetic modification that is important for cellular development.1 Different members of the DNMT gene family are involved in de novo CpG methylation. The DNMT3A gene is located on chromosome 2p23.3 and codes for a DNA methyltransferase. Ley et al.1 and Yan et al.2 were able to unravel DNMT3A mutations (DNMT3Amut) in acute myeloid leukemia (AML), thus supporting a role for aberrant DNA methylation to contribute to the pathogenesis of this disease. Subsequent studies detected DNMT3Amut in 17–34% of AML with normal karyotype (CN-AML) (see Table 1). Depending on the respective patient cohort characteristics, occurrence of the mutations was associated with an inferior survival (Table 1). Subsequently, DNMT3Amut were studied and observed in other hematological malignancies (Table 1): mutation frequencies were reported to be 3–8% in myelodysplastic syndromes (MDS), 4% in chronic myelomonocytic leukemia (CMML), 10% in myeloproliferative neoplasms and 4% in immature adult T-cell acute lymphoblastic leukemia (T-ALL).

Table 1 Overview on DNMT3A mutation frequencies and prognostic impact in different hematological entities according to the results from this study and previous studies
Full size table

Thus far, DNMT3Amut were studied in independent large patient cohorts in AML, whereas only few data are available on other entities. Aiming to analyze the frequency of DNMT3Amut and their clinical impact in different hematological malignancies in more detail, we investigated a total of 511 cases. In detail, we analyzed 194 de novo CN-AML, 115 MDS, 103 CMML and 99 T-ALL cases (196 females, 315 males; median age: 66.6 years; range: 18.8–100.4 years). Clinical follow-up data were available in 451/511 patients. Patient characteristics are given in Supplementary Table 1. Of note, a total of 315 cases had been included in a previous study.3, 4

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Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Munich, Germany

    A Roller, V Grossmann, U Bacher, F Poetzinger, S Weissmann, N Nadarajah, L Boeck, W Kern, C Haferlach, S Schnittger, T Haferlach & A Kohlmann

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  1. A Roller
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Correspondence to A Kohlmann.

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Competing interests

WK, CH, SS and TH have equity ownership of MLL Munich Leukemia Laboratory GmbH. AR, VG, UB, FB, SW, NN, LB and AK are employed by the MLL Munich Leukemia Laboratory GmbH.

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Author contributions

AR and VG interpreted the data. AR, VG, and UB wrote the manuscript. VG designed the study. VG, AK and SW performed molecular analysis. FP and LB provided technical assistance. AR and NN performed bioinformatics. WK, CH, SS and TH provided assistance in the design of the study, characterized patient samples and critically reviewed the manuscript. All authors approved the final version submitted for publication.

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Roller, A., Grossmann, V., Bacher, U. et al. Landmark analysis of DNMT3A mutations in hematological malignancies. Leukemia 27, 1573–1578 (2013). https://doi.org/10.1038/leu.2013.65

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