The E3 ligase TRIM31 regulates hematopoietic stem cell homeostasis and MLL-AF9 leukemia.
The E3 ligase TRIM31 regulates hematopoietic stem cell homeostasis and MLL-AF9 leukemia.
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E3连接酶TRIM 31调节造血干细胞稳态和MLL-AF 9白血病。
DOI：
10.3324/haematol.2022.281955
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发表时间：
2023-08-01
期刊：
影响因子：
10.1
通讯作者：
Diao, Daojun
中科院分区：
文献类型：
--
作者：
Zhang, Kai;Liu, Dingdong;Li, Yafei;Shi, Zhencan;Guo, Jun;Gao, Chengjiang;Wang, Hu;Ju, Zhenyu;Diao, Daojun
造血干细胞（HSC）保持在静止状态，以维持其自我更新能力。细胞周期蛋白依赖性激酶（CDK）和细胞周期蛋白的适当调节是维持HSC稳态的关键。在这里，我们发现E3连接酶TRIM 31通过CDK 8的积累调节HSC稳态和白血病。TRIM 31缺陷促进造血干细胞和祖细胞增殖和长期HSC耗竭。一系列竞争性移植试验表明TRIM 31缺陷的HSC表现出受损的重建能力。TRIM 31缺失导致小鼠在应激条件下（5-氟尿嘧啶给药）的存活率较低，这与造血干细胞和祖细胞数量较少相关。在急性髓性白血病的鼠模型中，在TRIM 31缺失后白血病的起始显著加速。从机制上讲，我们发现泛素介导的CDK 8降解受到TRIM 31缺失的损害，这进一步诱导了PBX 1和细胞周期蛋白D1的转录表达。总之，这些发现揭示了TRIM 31在调节HSC稳态和白血病起始中的功能，并表明TRIM 31在白血病发展的早期阶段的生理重要性。
Hematopoietic stem cells (HSC) are kept in a quiescent state to maintain their self-renewal capacity. Proper regulation of cyclin-dependent kinases (CDK) and cyclin proteins is critical for the maintenance of HSC homeostasis. Here, we found that the E3 ligase, TRIM31, regulates HSC homeostasis and leukemia through the accumulation of CDK8. TRIM31 deficiency promotes hematopoietic stem and progenitor cell proliferation and long-term HSC exhaustion. Serial competitive transplantation assays showed that TRIM31-deficient HSC exhibit impaired reconstitution ability. TRIM31 loss led to a lower rate of survival of mice under conditions of stress (5-fluorouracil administration), which was correlated with a lower number of hematopoietic stem and progenitor cells. In a murine model of acute myeloid leukemia, the initiation of leukemia was significantly accelerated upon TRIM31 deletion. Mechanistically, we found that ubiquitin-mediated degradation of CDK8 was impaired by TRIM31 deletion, which further induced transcriptional expression of PBX1 and cyclin D1. Taken together, these findings reveal the function of TRIM31 in the regulation of HSC homeostasis and leukemia initiation, and indicate the physiological importance of TRIM31 in the early stage of the development of leukemia.
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