The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors

• DOI: 10.1038/s41467-022-31155-0
• Publication Date: 2022-07-04T03:16:44Z
• Authors: Lina Liu; Ana Vujovic; Nandan P. Deshpande; Shashank Sathe; Govardhan Anande; He Tian Tony Chen; Joshua Xu; Mark D. Minden; Gene W. Yeo; Ashwin Unnikrishnan; Kristin J. Hope; Yu Lu
• Keywords: ribosome biogenesis; Splicing factor; Nonsense-Mediated Decay

Abstract Chemo-resistance in acute myeloid leukemia (AML) patients is driven by leukemic stem cells (LSCs) resulting high rates of relapse and low overall survival. Here, we demonstrate that upregulation the splicing factor, RBM17 preferentially marks sustains LSCs directly correlates with shorten patient knockdown primary AML leads to differentiation impaired colony formation vivo engraftment. Integrative multi-omics analyses show repression inclusion poison exons production nonsense-mediated decay (NMD)-sensitive transcripts for pro-leukemic factors translation initiation EIF4A2. We EIF4A2 enriched its inhibition impairs progenitor activity. Proteomic analysis -depleted shows recapitulation biological effects, including pronounced suppression proteins involved ribosome biogenesis. Overall, these results provide a rationale target and/or downstream NMD-sensitive substrates treatment.