Targeting RIOK2 ATPase activity leads to decreased protein synthesis and cell death in acute myeloid leukemia Journal Article
| Authors: | Messling, J. E.; Agger, K.; Andersen, K. L.; Kromer, K.; Kuepper, H. M.; Lund, A. H.; Helin, K. |
| Article Title: | Targeting RIOK2 ATPase activity leads to decreased protein synthesis and cell death in acute myeloid leukemia |
| 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. © 2022 American Society of Hematology |
| Keywords: | adult; controlled study; unclassified drug; human cell; doxorubicin; nonhuman; flow cytometry; mouse; cell survival; apoptosis; cell growth; animal experiment; in vivo study; in vitro study; tumor xenograft; protein synthesis; leukemia cell; polysome; adenosine triphosphatase; cre recombinase; genomic dna; dna isolation; ribosome; acute myeloid leukemia; puromycin; high throughput sequencing; guide rna; human; article; rna sequencing; crispr-cas9 system; rio kinase 2 |
| Journal Title: | Blood |
| Volume: | 139 |
| Issue: | 2 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-01-13 |
| Start Page: | 245 |
| End Page: | 255 |
| Language: | English |
| DOI: | 10.1182/blood.2021012629 |
| PUBMED: | 34359076 |
| PROVIDER: | scopus |
| PMCID: | PMC8759535 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2022 -- Source: Scopus |
