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ACUTE MYELOID LEUKEMIA

Targeting leukemia-specific dependence on the de novo purine synthesis pathway

Leukemia volume 36, pages 383–393 (2022)Cite this article

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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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Fig. 1: Genome-wide CRISPR-Cas9 screens identify PAICS as an AML essential gene.
Fig. 2: PAICS knockdown slows AML cell proliferation.
Fig. 3: PAICS inhibitor suppresses AML cell proliferation.
Fig. 4: CRISPR screens in the presence of PAICS inhibitor identify genes whose loss interacts with drug.
Fig. 5: PAICS inhibitor treatment has anti-leukemia effects in AML PDX models.

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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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Authors and Affiliations

  1. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan

    Takuji Yamauchi, Kohta Miyawaki, Yuichiro Semba, Jumpei Nogami, Fumihiko Nakao, Takeshi Sugio, Kensuke Sasaki & Koichi Akashi

  2. Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, 812-8582, Japan

    Takuji Yamauchi, Takeshi Sugio & Takahiro Maeda

  3. Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Masatomo Takahashi, Yoshihiro Izumi & Takeshi Bamba

  4. Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, 02129, USA

    Luca Pinello

  5. Department of Pathology, Harvard Medical School, Boston, Massachusetts, 02129, USA

    Luca Pinello

  6. Division of Hematology/Oncology, Boston Children’s Hospital/Harvard Medical School, Boston, MA, 02115, USA

    Daniel E. Bauer

  7. Division of Precision Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan

    Takahiro Maeda

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  1. Takuji Yamauchi
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Contributions

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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Correspondence to Takahiro Maeda.

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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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