Highlights d yylncRNAs are divergently expressed with transcripts from cell fate regulatory gene loci d yylncT is a yylncRNA encoded by and physically associated with the active T locus d yylncT binds DNMT3B and affects DNA methylation at the active T locus d yylncT is essential for mesoderm commitment of human PSCs

KDM4 and JMJD2 are histone demethylases that are considered promising targets for treatment of MLL translocation–bearing acute myeloid leukemia. Agger and colleagues demonstrate an important role of KDM4 activity in long-term normal hematopoiesis that should be considered when contemplating the clinical use of long-term inhibition of KDM4 demethylase activity.

Novel therapies for the treatment of acute myeloid leukemia (AML) are urgently needed as current treatments do not cure the majority of AML patients. Here, we report on a domain-focused, kinome-wide CRISPR-Cas9 screen to identify protein kinase targets for the treatment of AML, which led to the identification of Rio-kinase 2 (RIOK2) as a potential novel target. We show that loss of RIOK2 leads to a decrease in protein synthesis and to ribosomal instability followed by apoptosis in leukemic cells, but not in fibroblasts. Moreover, we demonstrate that the ATPase function of RIOK2 is required for cell survival. By using a small molecule inhibitor, we show that pharmacological inhibition of RIOK2 similarly leads to loss of protein synthesis and apoptosis and affects leukemic cell growth in vivo. Our results provide proof-of-concept for targeting RIOK2 as a potential treatment for AML patients.