Abstract
Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
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Acknowledgements
We thank the members of the Department of Medicine and Biosystemic Science at Kyushu University for assistance, advice, and helpful discussion and Simon Osborne, Craig Southern, Debra Taylor, and Kevin Buchan from LifeArc for providing MRT00252040, and Elise Lamar for critical reading of the manuscript. This work is supported in part by a Grant-in-Aid for Young Scientists (19K17859), Research Grant of KANAE Foundation, MSD Life Science Foundation, The Yasuda Medical Foundation, Mochida Memorial Foundation for medical and pharmaceutical research, The Shinnihon Foundation of Advanced Medical Treatment Research, Takeda Science Foundation (to TY), a Grant-in-Aid for Scientific Research (S)(16H06391)(to KA) and an American Society of Hematology Bridge Grant, a Grant-in-Aid for Scientific Research (A) (17H01567), Grant-in-Aid for Scientific Research (S) (20H05699), and AMED under grant number 18063889 (to TM).
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TY, YS, FN, and TM designed CRISPR-Cas9 screen experiments. TY, YS, JN, and TM reviewed CRISPR screen data. TY, KM TS, and KS executed CRISPR-Cas9 experiments, cell biology experiments, and in vivo mouse studies (supervised by KA and TM). MT, YI, and TB performed metabolomic assays. YS and JN analyzed CRISPR saturation mutagenesis data (supervised by LP and DB). TY and TM wrote the manuscript with help from all authors.
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Yamauchi, T., Miyawaki, K., Semba, Y. et al. Targeting leukemia-specific dependence on the de novo purine synthesis pathway. Leukemia 36, 383–393 (2022). https://doi.org/10.1038/s41375-021-01369-0
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DOI: https://doi.org/10.1038/s41375-021-01369-0