The E3 ligase TRIM31 regulates hematopoietic stem cell homeostasis and MLL-AF9 leukemia

Abstract

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.