The problem we focused
Acute myeloid leukemia (AML) is identified as an aggressive disorder of the hematologic system, of which the 5-year survival rate of adult AML patients is only 24% (1, 2). The reason of the high recurrence and mortality of AML even after receiving various treatments is due to the low response of leukemia stem cells (LSCs) (3, 4). Given that hematopoietic stem cells (HSCs) share many common characteristics and signalling pathways with LSCs and AML patients also have normal HSCs in vivo, it is therefore important to explore how to selectively target LSCs without apparent toxicity to HSCs.
In this study, we showed that Thymocyte-expressed, positive selection-associated 1 (Tespa1) is dispensable for normal hematopoiesis but its deficiency prominently inhibits AML progression. Hence, exploring potential Tespa1 inhibitors may be a potential avenue to deal with the problem we focused. Notably, the inhibitors should be used with caution to protect the function of normal HSCs in AML patients when exposed to stress stimuli, due to the findings that stress may upregulate the expression of Tespa1 in normal HSCs and its deficiency may affect hematopoiesis under stress conditions.
What did we show?
We firstly noticed that Tespa1, a thymus specifically expressed gene, was also expressed in HSCs and its expression was significantly upregulated after stress. Although loss of Tespa1 had no obvious effect on normal hematopoiesis, its deletion promoted short-term HSC expansion under hematopoietic stresses (Figure 1).
Figure 1. Tespa1 deficiency facilitates HSC expansion upon short-term stress.
To evaluate whether Tespa1 deletion influences long-term HSC maintenance, we then analyzed the hematopoietic phenotype in middle-aged Tespa1+/+ and Tespa1-/- mice. It was observed that Tespa1 ablation significantly reduced the number of HSCs in 12-month-old mice. In addition, we performed a competitive BM transplantation (BMT) assay and found that Tespa1 deficiency impaired the long-term self-renewal capacity of HSCs (Figure 2).
Figure 2. Loss of Tespa1 impairs the long-term HSC maintenance.
To investigate whether TESPA1 is also involved in the regulation of AML biology, we analyzed its expression in AML samples and healthy controls from The Cancer Genome Atlas (TCGA) database. A significantly elevated expression of TESPA1 was observed in AML cells in comparation with controls. In addition, AML patients with higher expression of TESPA1 displayed increased relapse rate. More importantly, TESPA1 knockdown significantly suppressed primary human AML cell growth (Figure 3).
Figure 3. TESPA1 is essential for human AML cell growth.
To comprehensively understand the role of Tespa1 in leukemogenesis, we employed the MLL-AF9-induced murine AML model. Tespa1 deficiency substantially prolonged AML mice survival and reduced the percentage of GFP+ leukemic cells in the PB and BM of AML mice. Furthermore, we found that the numbers of GFP+ c-Kit+ cells and LSCs were evidently reduced in AML mice after Tespa1 deletion (Figure 4).
Figure 4. Tespa1 drives murine AML progression and maintains LSC function.
What are the implications of our study?
In conclusion, we demonstrate that loss of Tespa1 promotes short-term expansion but long-term exhaustion of HSCs under stress conditions and delays the progression of AML. Consequently, our data uncover a key role of Tespa1 in regulating the maintenance of HSCs and LSCs, therefore providing a new target for hematopoietic regeneration and AML treatment.
1. Yi M, Li A, Zhou L, Chu Q, Song Y, Wu K. The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: estimates based on the global burden of disease study 2017. J Hematol Oncol. 2020;13:72.
2. Yan H, Wang Z, Sun Y, Hu L, Bu P. Cytoplasmic NEAT1 Suppresses AML Stem Cell Self-Renewal and Leukemogenesis through Inactivation of Wnt Signaling. Adv Sci (Weinh). 2021;8:e2100914.
3. Shlush LI, Mitchell A, Heisler L, Abelson S, Ng SWK, Trotman-Grant A, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547:104-8.
4. Rautenberg C, Germing U, Haas R, Kobbe G, Schroeder T. Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment. Int J Mol Sci. 2019;20:228.