Background: Post-transcriptional modifications of rRNAs play important roles in biogenesis and function of ribosome. Results: NAT10 is an ATP-dependent RNA acetyltransferase responsible for N 4 -acetylcytidine formation of 18 S rRNA. Conclusion: NAT10 and ac 4 C1842 are required for pre-18 S rRNA processing. Significance: 40 S subunit formation is regulated by a single acetylation of 18 S rRNA, implying a regulatory mechanism for ribosome biogenesis by sensing the cellular energy budget.

Nagase and Inoue et al. generated a novel Asxl1 mutant mouse model to mimic clonal hematopoiesis and myelodysplastic syndromes caused by ASXL1 mutations and elucidated the effects of mutant versus wild-type ASXL1 on hematopoiesis, gene expression, and chromatin state.

Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and associated with adverse survival yet the molecular pathogenesis of ASXL1 mutations are not fully understood. Recently it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1 mutations (ASXL1-MT) inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SETBP1 mutations (SETBP1-MT) are enriched among patients with ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation as well as shorter survival, suggesting SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited Pp2a activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1 mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis, and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing AML in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the TGF-β signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

Agonistic antibodies targeting CD137 have been clinically unsuccessful due to systemic toxicity. Since conferring tumor selectivity through tumor-associated antigen limits its clinical use to cancers that highly express such antigen, we exploited extracellular adenosine triphosphate (exATP), which is a hallmark of the tumor microenvironment and highly elevated in solid tumors, as a broadly tumor selective switch. We generated a novel anti-CD137 switch antibody, STA551, which exerts agonistic activity only in the presence of exATP. STA551 demonstrated potent and broad anti-tumor efficacy against all mouse and human tumors tested and a wide therapeutic window without systemic immune activation in mice. STA551 was well tolerated even at 150 mg/kg/week in cynomolgus monkeys. These results provide a strong rationale for the clinical testing of STA551 against a broad variety of cancers regardless of antigen expression, and for the further application of this novel platform to other targets in cancer therapy.

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription.