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

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 () and Yu Lu ()
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Lina Liu: McMaster University
Ana Vujovic: University of Toronto
Nandan P. Deshpande: University of New South Wales
Shashank Sathe: University of California at San Diego
Govardhan Anande: University of New South Wales
He Tian Tony Chen: McMaster University
Joshua Xu: McMaster University
Mark D. Minden: University of Toronto
Gene W. Yeo: University of California at San Diego
Ashwin Unnikrishnan: University of New South Wales
Kristin J. Hope: University of Toronto
Yu Lu: McMaster University

Nature Communications, 2022, vol. 13, issue 1, 1-17

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

Date: 2022
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DOI: 10.1038/s41467-022-31155-0

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