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.

NUDT15编码核苷酸三磷酸二磷酸酶，负责代谢嘌呤类似物药物，其基因突变导致硫嘌呤治疗产生严重副作用。然而， Nudt15在白血病干细胞 (LSC) 和造血干细胞 (HSC) 中的功能仍不清楚。在这里，我们揭示了Nudt15调节小鼠 LSC 和 HSC 的自我更新。我们的数据显示， Nudt15负向调节小鼠白血病发生，其缺陷通过损害 LSC 自我更新来延长小鼠 AML 受体的生存，而Nudt15消融则显着增强小鼠 HSC 再生潜力和自我更新。从机制上讲， Nudt15调节小鼠 LSC 和 HSC 中的炎症信号传导，导致不同的自我更新结果。 Nudt15耗竭通过下调Ifi30抑制小鼠 LSC 自我更新，导致细胞内 ROS 水平升高。 Gata2是一种关键调节因子，是Nudt15介导小鼠 HSC 炎症信号传导所必需的。总的来说，我们的结果展示了Nudt15在通过炎症信号传导维持小鼠 LSC 和 HSC 功能方面的新的关键作用，并对临床意义有了新的见解。