Targeting RIOK2 ATPase activity leads to decreased protein synthesis and cell death in acute myeloid leukemia

• Published in: Blood Vol. 139; no. 2; pp. 245 - 255
• Main Authors: Messling, Jan-Erik, Agger, Karl, Andersen, Kasper L., Kromer, Kristina, Kuepper, Hanna M., Lund, Anders H., Helin, Kristian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-01-2022; American Society of Hematology
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Animals; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; CRISPR-Cas Systems; Gene Expression Regulation, Leukemic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Mice; Molecular Targeted Therapy; Myeloid Neoplasia; Protein Biosynthesis - drug effects; Protein Kinase Inhibitors - pharmacology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021012629

Novel therapies for the treatment of acute myeloid leukemia (AML) are urgently needed, because current treatments do not cure most patients with AML. We report a domain-focused, kinome-wide CRISPR-Cas9 screening that identified protein kinase targets for the treatment of AML, which led to the identification of Rio-kinase 2 (RIOK2) as a potential novel target. Loss of RIOK2 led to a decrease in protein synthesis and to ribosomal instability followed by apoptosis in leukemic cells, but not in fibroblasts. Moreover, the ATPase function of RIOK2 was necessary for cell survival. When a small-molecule inhibitor was used, pharmacological inhibition of RIOK2 similarly led to loss of protein synthesis and apoptosis and affected leukemic cell growth in vivo. Our results provide proof of concept for targeting RIOK2 as a potential treatment of patients with AML.
•CRISPR-Cas9 screening identified RIOK2 as a potential novel dependency target in AML.•Loss of RIOK2 catalytic activity led to stalled protein synthesis, ribosome degradation, and cell death.
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