Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML
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.
- Authors:
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[7];
[6];
[6];
[6];
[3];
[9];
[1];
[10];
more »
- Goethe Univ., Frankfurt (Germany); German Cancer Research Center, Heidelberg (Germany)
- Goethe Univ., Frankfurt (Germany); Univ. of Frankfurt (Germany)
- Goethe Univ., Frankfurt (Germany)
- Yale Univ., New Haven, CT (United States)
- Univ. Medicine Greifswald (Germany)
- Univ. Hospital Munster (Germany)
- Univ. Medical Center, Gottingen (Germany)
- Univ. of Frankfurt (Germany)
- Cambridge Univ. (United Kingdom)
- Univ. of Kent (United Kingdom)
- Goethe Univ., Frankfurt (Germany); Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Frankfurter (Germany)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1839753
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Oellerich, Thomas, Schneider, Constanze, Thomas, Dominique, Knecht, Kirsten M., Buzovetsky, Olga, Kaderali, Lars, Schliemann, Christoph, Bohnenberger, Hanibal, Angenendt, Linus, Hartmann, Wolfgang, Wardelmann, Eva, Rothenburger, Tamara, Mohr, Sebastian, Scheich, Sebastian, Comoglio, Federico, Wilke, Anne, Ströbel, Philipp, Serve, Hubert, Michaelis, Martin, Ferreirós, Nerea, Geisslinger, Gerd, Xiong, Yong, Keppler, Oliver T., and Cinatl, Jindrich. Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML. United States: N. p., 2019.
Web. doi:10.1038/s41467-019-11413-4.
Oellerich, Thomas, Schneider, Constanze, Thomas, Dominique, Knecht, Kirsten M., Buzovetsky, Olga, Kaderali, Lars, Schliemann, Christoph, Bohnenberger, Hanibal, Angenendt, Linus, Hartmann, Wolfgang, Wardelmann, Eva, Rothenburger, Tamara, Mohr, Sebastian, Scheich, Sebastian, Comoglio, Federico, Wilke, Anne, Ströbel, Philipp, Serve, Hubert, Michaelis, Martin, Ferreirós, Nerea, Geisslinger, Gerd, Xiong, Yong, Keppler, Oliver T., & Cinatl, Jindrich. Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML. United States. https://doi.org/10.1038/s41467-019-11413-4
Oellerich, Thomas, Schneider, Constanze, Thomas, Dominique, Knecht, Kirsten M., Buzovetsky, Olga, Kaderali, Lars, Schliemann, Christoph, Bohnenberger, Hanibal, Angenendt, Linus, Hartmann, Wolfgang, Wardelmann, Eva, Rothenburger, Tamara, Mohr, Sebastian, Scheich, Sebastian, Comoglio, Federico, Wilke, Anne, Ströbel, Philipp, Serve, Hubert, Michaelis, Martin, Ferreirós, Nerea, Geisslinger, Gerd, Xiong, Yong, Keppler, Oliver T., and Cinatl, Jindrich. Fri .
"Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML". United States. https://doi.org/10.1038/s41467-019-11413-4. https://www.osti.gov/servlets/purl/1839753.
@article{osti_1839753,
title = {Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML},
author = {Oellerich, Thomas and Schneider, Constanze and Thomas, Dominique and Knecht, Kirsten M. and Buzovetsky, Olga and Kaderali, Lars and Schliemann, Christoph and Bohnenberger, Hanibal and Angenendt, Linus and Hartmann, Wolfgang and Wardelmann, Eva and Rothenburger, Tamara and Mohr, Sebastian and Scheich, Sebastian and Comoglio, Federico and Wilke, Anne and Ströbel, Philipp and Serve, Hubert and Michaelis, Martin and Ferreirós, Nerea and Geisslinger, Gerd and Xiong, Yong and Keppler, Oliver T. and Cinatl, Jindrich},
abstractNote = {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.},
doi = {10.1038/s41467-019-11413-4},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {Fri Aug 02 00:00:00 EDT 2019},
month = {Fri Aug 02 00:00:00 EDT 2019}
}
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Works referencing / citing this record:
SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
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