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ACUTE MYELOID LEUKEMIA

Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia

Leukemia volume 39, pages 98–111 (2025)Cite this article

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Abstract

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy requiring novel treatment strategies. In this study, we identified phosphodiesterase 3 A (PDE3A) as a potential new target for drug repositioning in AML. PDE3A was preferentially overexpressed in AML cells than in normal cells, and high expression of PDE3A was correlated with lower event-free survival (EFS) in de novo AML patients. The PDE3A inhibitor anagrelide (ANA) profoundly suppresses the proliferation of high PDE3A-expressing AML cells while exhibiting minimal impact on those with low PDE3A expression. Moreover, synergistic effect of ANA with other chemotherapeutic drugs in high PDE3A expression AML cells was observed. The ANA-idarubicin (IDA) combination showed the most remarkable synergistic effect among all ANA-chemotherapeutic drugs commonly used in AML cell line models. Mechanistically, the synergy between ANA and IDA inhibited the survival of PDE3Ahigh AML cell lines through pyroptosis. This mechanism was initiated by GSDME cleavage triggered by caspase-3 activation. In vivo combination treatment of leukemic animals with high PDE3A expression significantly reduced leukemia burden and prolonged survival time compared with single-drug and vehicle control treatments. Our findings suggest that combined ANA and IDA treatment is an innovative and promising therapeutic strategy for AML patients with high PDE3A expression.

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Fig. 1: Significantly higher expression of PDE3A in AML cells and its correlation with poor prognosis.
Fig. 2: PDE3A inhibitors specifically inhibiting the growth of high PDE3A-expressing AML cells.
Fig. 3: ANA suppressing the proliferation of high PDE3A-expressing AML cell lines by interrupting the cell cycle and inhibiting colony-forming capacity.
Fig. 4: Targeting PDE3A to downregulate the MAPK signaling pathway in high PDE3A-expressing AML cells.
Fig. 5: ANA combined with IDA showing a notable synergistic effect in AML cells.
Fig. 6: ANA combined with IDA synergistically inhibiting the growth of high PDE3A-expressing AML cells through pyroptosis.
Fig. 7: Combination of ANA with IDA exerting synergistic anti-leukemia effects on AML xenograft mouse model.

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Data availability

Our sequencing and processed data files were submitted to the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) repository GSE269021 (RNA-seq). Other relevant data are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank the editor, April Jade, servicing at www.editage.cn who provided a deep revision of the manuscript.

Funding

This study was supported by the following grants: The National Key Research and Development Program of China (no. 2022YFC2502700), Jiangsu Key project, BE2021654 to Shaoyan Hu, the National Natural Science Foundation of China (NSFC 82100229 to Yuanyuan Tian, 82200177 to Li Gao, 82170218, and 81970163 to Shaoyan Hu, 31830051 and 32370810 to Sudan He), and Suzhou Projects (GSWS2020039, 2020ZKPB02 to Shaoyan Hu, GSWS 2023048 to Yixin Hu), and the Suzhou Municipal Key Laboratory (SZS201615,SZS2023014 to Shaoyan Hu, SZS2022005 to Sudan He), and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2022-I2M-2-004, 2021-I2M-1-041, 2021-I2M-1-047, and 2021-I2M-1-061), and the NCTIB Fund for R&D platform for Cell and Gene Therapy.

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Author notes

  1. These authors contributed equally: Chenwei Yang, Yixin Hu, Li Gao, Zhiheng Li.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Children’s Hospital of Soochow University, Suzhou, 215000, China

    Chenwei Yang, Yixin Hu, Li Gao, Yongping Zhang, Hu Liu, Qi Ji, Minyuan Liu, Jun Lu, Peifang Xiao & Shaoyan Hu

  2. Institution of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, 215000, China

    Zhiheng Li, Jian Pan & Yuanyuan Tian

  3. Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, 215000, China

    Ran Zhuo

  4. State Key Laboratory of Common Mechanism Research for Major Diseases and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China

    Yayun Du & Sudan He

  5. Department of Transfusion Medicine, Children’s Hospital of Soochow University, Suzhou, 215000, China

    Jing Ling

  6. Jiangsu Pediatric Hematology & Oncology Center, Jiangsu, China

    Shaoyan Hu

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Contributions

C.Y., X.H., and Y.T. conceived the study and analyzed data; C.Y. and Z.L. performed RNA-seq; C.Y. and M.L. performed the western blotting procedure; C.Y. and R.Z. performed animal studies; S.H., C.Y., J.L., L.G., Y.Z., H.L., Y.D., and Q.J. provided clinical AML samples and collected patient information; L.G., and C.Y. conceived the experiments, S.H., Y.T., J.P., and J.L. helped organize the paper and conceived the experiments, C.Y., Y.T., P.X. S.H., and S.H. designed the study and wrote the manuscript.

Corresponding authors

Correspondence to Yuanyuan Tian, Sudan He, Jing Ling or Shaoyan Hu.

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The authors declare no competing interests.

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Patient: This study was approved by the Ethics Committee of the Children’s Hospital of Soochow University (No. 2017047-3) and was in accordance with Declaration of Helsinki. Informed consent was obtained from the parents or legal guardians and participants. Animal: All animal experiments were conducted in compliance with the animal care guidelines approved by the Institutional Laboratory Animal Care and Use Committee of Soochow University (SUDA20230802A05) and were in accordance with the ARRIVE guidelines.

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Yang, C., Hu, Y., Gao, L. et al. Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia. Leukemia 39, 98–111 (2025). https://doi.org/10.1038/s41375-024-02437-x

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