Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML

Thomas Oellerich, Constanze Schneider, Dominique Thomas, Kirsten M. Knecht, Olga Buzovetsky, Lars Kaderali, Christoph Schliemann, Hanibal Bohnenberger, Linus Angenendt, Wolfgang Hartmann, Eva Wardelmann, Tamara Rothenburger, Sebastian Mohr, Sebastian Scheich, Federico Comoglio, Anne Wilke, Philipp Ströbel, Hubert Serve, Martin Michaelis, Nerea Ferreirós, Gerd Geisslinger, Yong Xiong, Oliver T. Keppler () and Jindrich Cinatl ()
Additional contact information
Thomas Oellerich: Goethe University of Frankfurt
Constanze Schneider: Goethe University of Frankfurt
Dominique Thomas: Goethe University of Frankfurt
Kirsten M. Knecht: Yale University
Olga Buzovetsky: Yale University
Lars Kaderali: University Medicine Greifswald
Christoph Schliemann: University Hospital Münster
Hanibal Bohnenberger: University Medical Center
Linus Angenendt: University Hospital Münster
Wolfgang Hartmann: University Hospital Münster
Eva Wardelmann: University Hospital Münster
Tamara Rothenburger: University of Frankfurt
Sebastian Mohr: Goethe University of Frankfurt
Sebastian Scheich: Goethe University of Frankfurt
Federico Comoglio: Cambridge University
Anne Wilke: Goethe University of Frankfurt
Philipp Ströbel: University Medical Center
Hubert Serve: Goethe University of Frankfurt
Martin Michaelis: University of Kent
Nerea Ferreirós: Goethe University of Frankfurt
Gerd Geisslinger: Goethe University of Frankfurt
Yong Xiong: Yale University
Oliver T. Keppler: University of Frankfurt
Jindrich Cinatl: University of Frankfurt

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11413-4

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