Double mutant DNMT3A AML: a unique subtype experiencing increased DNA damage and poor prognosis.

Mutation of DNMT3A, encoding a de novo methyltransferase essential for cytosine methylation, is a common early event in clonal hematopoiesis (CH) and adult acute myeloid leukemia (AML). Spontaneous deamination of methylated cytosines damages DNA, which is repaired by the base excision repair (BER) enzymes methyl-CpG binding domain 4 (MBD4) and thymine DNA glycosylase (TDG). Congenital MBD4 deficiency has been linked to early-onset CH and AML and is marked by exceedingly high levels of DNA damage and mutation of DNMT3A. Strikingly, wild-type (WT) DNMT3A binds TDG, thereby potentiating its repair activity. Because TDG is the only remaining BER enzyme in MBD4-deficient patients with AML capable of repairing methylation damage, we investigated whether mutant DNMT3A negatively affects the repair function of TDG. We found that, although WT DNMT3A stimulates TDG function, mutant DNMT3A impairs TDG-mediated repair of DNA damage in vitro. In light of this finding and to extrapolate our observations to the broader AML patient population, we investigate here the genetic profiles and survival outcomes of patients with AML with single mutant (SM) vs double mutant (DM) DNMT3A. Patients with DM DNMT3A AML show a characteristic driver mutation landscape and reduced overall survival compared with patients with SM DNMT3A AML. Importantly, whole-genome sequencing showed a trend for increased DNA damage in primary DM DNMT3A AML samples, especially when DNMT3A mutations are located at the DNMT3A-TDG interaction interface. © 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Citation

Emma L Boertjes, Sanne Massaar, Annelieke Zeilemaker, Jolinda Konijnenburg, Melissa Rijken, François G Kavelaars, Tim Grob, Jurjen Versluis, Bob Löwenberg, Peter J M Valk, Mathijs A Sanders. Double mutant DNMT3A AML: a unique subtype experiencing increased DNA damage and poor prognosis. Blood advances. 2025 Mar 25;9(6):1344-1355

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PMID: 39693514

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