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

Author:

Messling Jan-Erik12ORCID,Agger Karl12,Andersen Kasper L.1ORCID,Kromer Kristina12,Kuepper Hanna M.12,Lund Anders H.1,Helin Kristian1234ORCID

Affiliation:

1. Biotech Research and Innovation Centre and

2. The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark; and

3. Cell Biology Program and

4. Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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