%0 Journal Article
%A Greve, Gabriele
%A Andrieux, Geoffroy
%A Schlosser, Pascal
%A Blagitko-Dorfs, Nadja
%A Rehman, Usama-Ur
%A Ma, Tobias
%A Pfeifer, Dietmar
%A Heil, Gerhard
%A Neubauer, Andreas
%A Krauter, Jürgen
%A Heuser, Michael
%A Salih, Helmut R
%A Döhner, Konstanze
%A Döhner, Hartmut
%A Hackanson, Björn
%A Börries, Melanie
%A Lübbert, Michael
%T In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts.
%J Leukemia
%V 37
%N 5
%@ 0887-6924
%C London
%I Springer Nature
%M DKFZ-2023-00713
%P 1018-1027
%D 2023
%Z 2023 May;37(5):1018-1027
%X Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1-5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37024521
%R 10.1038/s41375-023-01876-2
%U https://inrepo02.dkfz.de/record/275344