期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-31155-0
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资金
- Canadian Institutes for Health Research Doctoral Research Award
- National Health & Medical Research Council (Australia) [APP1163815]
- Leukemia & Lymphoma Society
- Leukemia Foundation
- Snowdome Foundation [6589-20]
- Ontario Institute for Cancer Research Investigator Award [IA-033]
- Canadian Institutes for Health Research [PJT-156158]
- NIH [R01 HL137223]
- Canadian Natural Science and Engineering Research Council [RGPIN-2017-06159]
- Cancer Research Society Operating Grant [24278]
- Canada Foundation for Innovation JELF [35544]
- Ontario Ministry of Economic Development, Job Creation and Trade ORF-RI [35544]
- Marta and Owen Boris Foundation
The splicing factor RBM17 supports leukemic stem cells (LSCs) in acute myeloid leukemia (AML) by avoiding nonsense-mediated decay of pro-leukemic factors such as the translation initiation factor EIF4A2. Targeting RBM17 and its downstream NMD-sensitive splicing substrates may provide a therapeutic strategy for AML treatment.
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. Leukemic stem cells (LSCs) drive chemoresistance and relapse in acute myeloid leukemia. Here, the authors show that the splicing factor RBM17 supports LSCs through avoiding nonsense-mediated decay of pro-leukaemic factors such as the translation initiation factor EIF4A2.
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