RBM17 Mediates Evasion of Pro-Leukemic Factors from Splicing-coupled NMD to Enforce Leukemic Stem Cell Maintenance

ABSTRACT: Acute myeloid leukemia (AML) patients suffer from chemo-resistance, high relapse frequency, and low overall survival rate, outcomes driven by leukemic stem cells (LSCs). Understanding the molecular mechanisms that support these primitive leukemic cells is crucial for developing effective AML therapeutics. In the present study, we demonstrate that upregulation of the splicing factor RBM17 preferentially marks and sustains the primitive compartment of AML. RBM17 expression is significantly higher in LSCs and its levels in human AML directly correlate with shortened survival in patients with the disease. RBM17 knockdown in primitive primary AML cells leads to myeloid differentiation and the impairment of their in vitro colony forming and in vivo engraftment capacities. To study the molecular mechanisms underlying the functional roles of RBM17 in AML, we performed global profiling of the RBM17-RNA interactome and proteome changes downstream of RBM17 knockdown. Through these integrative multi-omics analyses, we show that RBM17 repression leads to inclusion of poison exons and production of nonsense-mediated decay (NMD)-sensitive transcripts for pro-leukemic factors such as RBM39 and EZH2, along with the translation initiation factor EIF4A2. We further show that EIF4A2 expression is enriched in LSCs and inhibition of EIF4A2 impairs primary AML progenitor activity. Proteome analysis of AML cells after EIF4A2 knockdown demonstrate that EIF4A2 repression largely recapitulates the biological effect of RBM17 knockdown including the 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 in primitive leukemic cells for AML treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180955 | GEO | 2022/04/26

REPOSITORIES: GEO