학술논문
In vivo kinetics of early, non-random methylome and transcriptome changes induced by DNA-hypomethylating treatment in primary AML blasts
Document Type
Article
Author
Greve, Gabriele; Andrieux, Geoffroy; Schlosser, Pascal; Blagitko-Dorfs, Nadja; Rehman, Usama-Ur; Ma, Tobias; Pfeifer, Dietmar; Heil, Gerhard; Neubauer, Andreas; Krauter, Jürgen; Heuser, Michael; Salih, Helmut R.; Döhner, Konstanze; Döhner, Hartmut; Hackanson, Björn; Boerries, Melanie; Lübbert, Michael
Source
Leukemia; May 2023, Vol. 37 Issue: 5 p1018-1027, 10p
Subject
Language
ISSN
08876924; 14765551
Abstract
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/m2day 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.