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

• Published in: Nature communications Vol. 10; no. 1; pp. 3475 - 14
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 13/89; 5-aza-2'-deoxycytidine; 60 APPLIED LIFE SCIENCES; 631/67; 692/4028; 692/53; 82/51; 82/58; 96/2; Ablation; Acute myeloid leukemia; Animals; Anticancer properties; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Azacitidine - therapeutic use; Azacytidine; Biomarkers; Biomarkers, Tumor - metabolism; Bone marrow; Bone Marrow - pathology; Cell culture; Cell Line, Tumor; Deactivation; Decitabine - pharmacology; Decitabine - therapeutic use; DNA Methylation - drug effects; Drug Resistance, Neoplasm - drug effects; Female; Gene Expression Regulation, Leukemic - drug effects; Humanities and Social Sciences; Humans; Inactivation; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Metabolites; Mice; multidisciplinary; Myeloid leukemia; Patient Selection; Patients; Primary Cell Culture; Retrospective Studies; SAM Domain and HD Domain-Containing Protein 1 - metabolism; Science; Science (multidisciplinary); Substrates; Treatment Outcome; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation

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...