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Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia

Oncogene volume 42, pages 3331–3343 (2023)Cite this article

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Abstract

The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD+) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD+ AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD+ AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.

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Fig. 1: DHODH blockade induces degradation of FLT3-ITD protein.
Fig. 2: DHODH blockade triggers autophagy-mediated FLT3-ITD downregulation.
Fig. 3: The activation of mTORC1 is abolished by DHODH blockade.
Fig. 4: DHODH inhibitor BAY-234 sensitizes AML cells harboring FLT3-ITD mutation to quizartinib in vitro.
Fig. 5: Co-treatment of BAY-234 and quizartinib promote tumor regression and prolong survival in mice.
Fig. 6: BAY-234 overcomes mutation-driven resistance to quizartinib in AML.

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All data generated or analyzed during this study are included in this published paper and its supplementary information file.

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (81973362, 82173857), Shanghai Committee of Science and Technology (22S11900900), Guangdong Provincial Medical Science and Technology Research Fund (B2021077) and Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism. We thank the Ministry of Education and the Research Center of Analysis and Test of East China University of Science and Technology.

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  1. These authors contributed equally: Hui Ma, Jiayan Cui, Zehui Liu.

Authors and Affiliations

  1. Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China

    Hui Ma, Jiayan Cui, Zehui Liu, Wenqing Fang, Sisi Lu, Shuying Cao, Yuanyuan Zhang & Jin Huang

  2. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 201203, Shanghai, China

    Ji-An Chen, Lixue Lu, Qiong Xie & Yonghui Wang

  3. NMPA Key Laboratory of Rapid Drug Inspection Technology, Guangdong Institute for Drug Control, 510663, Guangzhou, China

    Ying Huang

  4. Department of Hematology, People’s Hospital Affiliated to Ningbo University, 315000, Ningbo, China

    Kongfei Li

  5. Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China

    Kongfei Li & Hongyan Tong

  6. Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, 310003, Hangzhou, China

    Kongfei Li & Hongyan Tong

  7. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 200241, Shanghai, China

    Weiqiang Lu

  8. Shanghai Key Laboratory of Multidimensional Information Processing, East China Normal University, 200241, Shanghai, China

    Weiqiang Lu

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Contributions

This work was conceptualized by HM, JYC, ZHL, WQL, and JH. Mouse model were performed by HM, JYC, ZHL. Cell culture, qPCR, confocal analysis, were done by HM, ZHL. Immunoblot analysis, electron microscopy analysis and plasmid construction experiments were performed by HM, ZHL, WQF, SSL, SYC, and YYZ. BAY-234 was provided by JAC, LXL, YHW, and QX. Bioinformatics analysis were done by HM and ZHL. Data analysis and interpretation were done by HM, JYC, ZHL, KFL, and HYT. The manuscript was drafted by HM, JYC, WQL, and JH, and reviewed and modified by all the authors.

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Correspondence to Jin Huang or Weiqiang Lu.

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All animal studies and protocols were approved by the Animal Experiments Committee of East China University of Science and Technology (ECUST-2021-03007).

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Ma, H., Cui, J., Liu, Z. et al. Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia. Oncogene 42, 3331–3343 (2023). https://doi.org/10.1038/s41388-023-02848-7

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