TY  - JOUR
A1  - Oellerich, Thomas
A1  - Schneider, Constanze
A1  - Thomas, Dominique Jeanette
A1  - Knecht, Kirsten M.
A1  - Buzovetsky, Olga
A1  - Kaderali, Lars
A1  - Schliemann, Christoph
A1  - Bohnenberger, Hanibal
A1  - Angenendt, Linus
A1  - Hartmann, Wolfgang
A1  - Wardelmann, Eva
A1  - Rothenburger, Tamara
A1  - Mohr, Sebastian
A1  - Scheich, Sebastian
A1  - Comoglio, Federico
A1  - Wilke, Anne
A1  - Ströbel, Philipp
A1  - Serve, Hubert
A1  - Michaelis, Martin
A1  - Ferreirós Bouzas, Nerea
A1  - Geisslinger, Gerd
A1  - Xiong, Yong
A1  - Keppler, Oliver Till
A1  - Cinatl, Jindrich
T1  - Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML
T2  - Nature Communications
N2  - Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia.
KW  - Biomarkers
KW  - Cancer
KW  - Oncology
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50754
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-507543
SN  - 2041-1723
N1  - Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
VL  - 10
IS  - 1, Art. 3475
SP  - 1
EP  - 14
PB  - Nature Publishing Group UK
CY  - [London]
ER  -