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Däther, M.* ; Peev, E.* ; Fröhlich, A. ; Vick, B. ; Fatourechi, S.* ; Gasparoni, G.* ; Heiss, M.* ; Pleintinger, C.C.* ; Bisong, E.A.* ; Hurmiz, H.* ; Guglielminotti, D.* ; Gärtner, Y.V.* ; Aumer, T.* ; Spiekermann, K.* ; Walter, J.* ; Jeremias, I. ; Traube, F.R.* ; Carell, T.*

Increasing TET expression and 5-hydroxymethylcytosine formation by a carbocyclic 5-Aza-2′-deoxy-cytidine antimetabolite.

Angew. Chem.-Int. Edit., DOI: 10.1002/anie.6265286 (2026)
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Open Access Hybrid
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Ten-eleven translocation (TET) enzymes are critical epigenetic regulators, which oxidize the methylated cytosine nucleobase 5-methyl-dC (mdC) in the genome to 5-hydroxymethyl-dC (hmdC) in an α-ketoglutarate-dependent manner. Because the presence of mdC in the promoter region of a given gene silences its expression, this oxidation goes in hand with the reactivation of such silenced genes. In different highly aggressive cancers such as acute myeloid leukemia (AML) and glioblastoma, loss of TET enzyme function, and therefore reduced hmdC levels pave the way for tumor development. Impairment of TET activity can occur through metabolic inhibition, through loss-of-function mutations in TET genes themselves, and finally through suppression of TET-expression via epigenetic silencing. Reactivation of TET enzyme expression represents a major aim of epigenetic cancer therapy. Here we show that the carbocyclic antimetabolite 5-aza-2′deoxycytidine (cAzadC), which is supposed to suppress the methylation of DNA during replication, leads to a substantial increase of TET2 expression and strongly increasing hmdC levels. We show that the treatment with cAzadC goes in hand with the broad reactivation of the cellular antitumor responses. With patient-derived xenograft AML-mouse models, we show that this translates into a strongly improved anticancer effect in vivo.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid Leukemia ; Decitabine ; Dna Hydroxymethylation ; Dna Methylation ; Dnmt Inhibition ; Epigenetics
ISSN (print) / ISBN 1433-7851
e-ISSN 1521-3773
Journal Angewandte Chemie - Internationale Edition
Publisher Wiley
Publishing Place Weinheim
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)