Abstract
Selinexor, a first-in-class exportin1 (XPO1) inhibitor, is an attractive anti-tumor agent because of its unique mechanisms of action; however, its dose-dependent toxicity and lack of biomarkers preclude its wide use in clinical applications. To identify key molecules/pathways regulating selinexor sensitivity, we performed genome-wide CRISPR/Cas9 dropout screens using two B-ALL lines. We identified, for the first time, that paralogous DDX19A and DDX19B RNA helicases modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export. While single depletion of either DDX19A or DDX19B barely altered MCL1 protein levels, depletion of both significantly attenuated MCL1 mRNA nuclear export, reducing MCL1 protein levels. Importantly, combining selinexor treatment with depletion of either DDX19A or DDX19B markedly induced intrinsic apoptosis of leukemia cells, an effect rescued by MCL1 overexpression. Analysis of Depmap datasets indicated that a subset of T-ALL lines expresses minimal DDX19B mRNA levels. Moreover, we found that either selinexor treatment or DDX19A depletion effectively induced apoptosis of T-ALL lines expressing low DDX19B levels. We conclude that XPO1 and DDX19A/B coordinately regulate cellular MCL1 levels and propose that DDX19A/B could serve as biomarkers for selinexor treatment. Moreover, pharmacological targeting of DDX19 paralogs may represent a potential strategy to induce intrinsic apoptosis in leukemia cells.
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Data availability
The processed data of CRISPR/Cas9 screens are available as a supplemental table. Raw data will be provided upon request.
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Acknowledgements
We thank the members of the Department of Medicine and Biosystemic Science and the Division of Precision Medicine at Kyushu University for assistance and helpful discussion and Elise Lamar for critical reading of the manuscript. This work is supported in part by a Grant-in-Aid for Young Scientists (18K16089) (to YS), a Grant-in-Aid for Young Scientists (19K17859), a Research Grant from the KANAE Foundation, the MSD Life Science Foundation, the Yasuda Medical Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Shinnihon Foundation of Advanced Medical Treatment Research, the Takeda Science Foundation (to TY), a Grant-in-Aid for Scientific Research (C)(23K07816) (to KS), a Grant-in-Aid for Young Scientists (22K16323) (to SH), a Grant-in-Aid for Scientific Research (S)(16H06391) (to K. Akashi), a Grant-in-Aid for Scientific Research (A) (17H01567, 20H00540), an AMED under grant number 18063889 and a Grant-in-Aid for Scientific Research (S)(20H05699) (to TM).
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TT, YS, TY, and TM designed CRISPR-Cas9 screen experiments. TT, YS, KS, TY, HI, TS. K. Akashi and TM reviewed CRISPR screen data. TT, KS, YS, TY, KS, SH, HI, and FN executed the CRISPR-Cas9 and cell biology experiments. K. Akahane and TI provided KOPN49 cells. TT and TM wrote the manuscript with help from all the authors.
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All experiments involving human material (leukemia cell lines) were performed in accordance with the Declaration of Helsinki under an approved Kyushu university institutional research protocol (#4-142). Informed consent from human research participants: not applicable.
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Terasaki, T., Semba, Y., Sasaki, K. et al. The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells. Leukemia 38, 1918–1928 (2024). https://doi.org/10.1038/s41375-024-02343-2
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DOI: https://doi.org/10.1038/s41375-024-02343-2
