造血干细胞（HSCs）和白血病干细胞（LSCs）具有强大的自我更新潜力，分别负责维持正常和恶性造血。尽管已经做出了相当努力探索HSC和LSC维持的调节，但其潜在的分子机制仍然不清楚。在这里，我们观察到，刘氏杂交瘤细胞-表达，正选择相关1（Tespa1）的表达在HSC在应激暴露后显著增加。值得注意的是，由于休息不良，Tespa1删除导致小鼠在应激条件下HSC短期扩张但长期筋疲力尽。机械上，Tespa1可以与CSN子单位6（CSN6）相互作用，CSN6是COP9信号体的一个子单位，以防止HSC中c-Myc蛋白通过泛素化介导降解。因此，强迫c-Myc表达可以改善Tespa1零HSC的功能缺陷。另一方面，Tespa1被发现在人急性髓系白血病（AML）细胞中高度富集，对AML细胞的生长至关重要。此外，使用MLL-AF9诱导的AML模型，我们发现Tespa1缺乏抑制了白血病发生和LSC维持。总之，我们的发现揭示了Tespa1在促进HSC和LSC维持中的重要作用，因此提供了造血再生和AML治疗的新见解。©2023年作者。

Hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have robust self-renewal potential, which is responsible for sustaining normal and malignant hematopoiesis, respectively. Although considerable efforts have been made to explore the regulation of HSC and LSC maintenance, the underlying molecular mechanism remains obscure. Here, we observe that the expression of thymocyte-expressed, positive selection-associated 1 (Tespa1) is markedly increased in HSCs after stresses exposure. Of note, deletion of Tespa1 results in short-term expansion but long-term exhaustion of HSCs in mice under stress conditions due to impaired quiescence. Mechanistically, Tespa1 can interact with CSN subunit 6 (CSN6), a subunit of COP9 signalosome, to prevent ubiquitination-mediated degradation of c-Myc protein in HSCs. As a consequence, forcing c-Myc expression improves the functional defect of Tespa1-null HSCs. On the other hand, Tespa1 is identified to be highly enriched in human acute myeloid leukemia (AML) cells and is essential for AML cell growth. Furthermore, using MLL-AF9-induced AML model, we find that Tespa1 deficiency suppresses leukemogenesis and LSC maintenance. In summary, our findings reveal the important role of Tespa1 in promoting HSC and LSC maintenance and therefore provide new insights on the feasibility of hematopoietic regeneration and AML treatment.© 2023. The Author(s).