Hematopoietic stem cells (HSCs) are kept in a quiescent state to maintain their self-renewal capacity. Proper regulation of cyclin-dependent kinases (CDKs) and cyclin proteins is critical for the maintenance of HSC homeostasis. Here, we found the E3 ligase-TRIM31 regulates HSC homeostasis and leukemia through the accumulation of CDK8. TRIM31 deficiency promotes hematopoietic stem and progenitor cell (HSPC) proliferation and long-term HSC exhaustion. Serial competitive transplantation assays showed that TRIM31-deficient HSCs exhibit impaired reconstitution ability. TRIM31 loss led to a lower mouse survival rate under stress conditions of 5-fluorouracil (5-FU) administration, which was correlated with a lower number of HSPCs. In a murine acute myeloid leukemia model, leukemia initiation 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 regulation of hematopoietic stem cell homeostasis and leukemia initiation; and indicate the physiological importance of TRIM31 in leukemia development at early stage of disease.
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