TY  - JOUR
AU  - Greve, Gabriele
AU  - Andrieux, Geoffroy
AU  - Schlosser, Pascal
AU  - Blagitko-Dorfs, Nadja
AU  - Rehman, Usama-Ur
AU  - Ma, Tobias
AU  - Pfeifer, Dietmar
AU  - Heil, Gerhard
AU  - Neubauer, Andreas
AU  - Krauter, Jürgen
AU  - Heuser, Michael
AU  - Salih, Helmut R
AU  - Döhner, Konstanze
AU  - Döhner, Hartmut
AU  - Hackanson, Björn
AU  - Börries, Melanie
AU  - Lübbert, Michael
TI  - In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts.
JO  - Leukemia
VL  - 37
IS  - 5
SN  - 0887-6924
CY  - London
PB  - Springer Nature
M1  - DKFZ-2023-00713
SP  - 1018-1027
PY  - 2023
N1  - 2023 May;37(5):1018-1027
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37024521
DO  - DOI:10.1038/s41375-023-01876-2
UR  - https://inrepo02.dkfz.de/record/275344
ER  -