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ACUTE MYELOID LEUKEMIA

Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis

Leukemia volume 38, pages 1958–1970 (2024)Cite this article

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Abstract

NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.

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Fig. 1: NUDT15 is required for maintaining AML LSC capacity.
Fig. 2: Nudt15 regulates inflammatory signaling pathways in LSCs.
Fig. 3: Ifi30/ROS signaling axis modulates Nudt15 functions on LSC self-renewal.
Fig. 4: Nudt15 is dispensable for normal hematopoiesis under homeostatic conditions.
Fig. 5: Nudt15 ablation enhances the self-renewal capacity of HSCs under stress conditions.
Fig. 6: Nudt15 negatively regulates HSC self-renewal through TNF-α/NFkB signaling pathway.
Fig. 7: Gata2 is required for Nudt15-regulating TNF-α/NFkB signaling in HSCs.

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Data availability

RNA-seq data that support the findings of this study are available in the National Center for Biotechnology information’s Gene Expression Omnibus, with accession number GSE269233.

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Acknowledgements

This research was supported in part by the National Natural Science Foundation of China (Grant No. 82070106), the Natural Science Foundation of Shanghai (Grant No. 18ZR1414900), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and Special Project of Science and Technology Plan of Shaoxing Science and Technology Bureau (Grant No. 2020B33004).

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Author notes

  1. These authors contributed equally: Jiachen Wang, Yu Zhang, Lei Li.

Authors and Affiliations

  1. School of Life Sciences, Shanghai University, Shanghai, 200444, China

    Jiachen Wang, Yu Zhang, Liujiao Wang, Bowu Wang, Yanwen Ge & Zhonghui Zhang

  2. Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Lei Li

  3. Qianweichang College, Shanghai University, Shanghai, 200444, China

    Shuainan Sun

  4. Shaoxing Institute of Technology, Shanghai University, Shaoxing, 312000, China

    Zhonghui Zhang

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Contributions

Z.Z. was responsible for experimental design, data analysis, and manuscript preparation; J.C.W, Y.Z., L.L., L.W., S.S, B.W., and G.W. performed experiments.

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Correspondence to Zhonghui Zhang.

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Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki. Human samples were obtained from the patients and healthy donors after acquiring written informed consent. All experimental protocols were approved by the Ethics Committee of Shanghai University (Approval number: ECSHU 2020-047).

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Wang, J., Zhang, Y., Li, L. et al. Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis. Leukemia 38, 1958–1970 (2024). https://doi.org/10.1038/s41375-024-02352-1

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