Mechanism of USP11 regulated SIRT3/ROS in drug resistance of acute myeloid leukemia

Acute myeloid leukemia (AML) represents a highly heterogeneous group of hematological malignancies. This study aims to elucidate the protective role of USP11 in mediating drug resistance in AML. We observed elevated USP11 mRNA expression levels in AML patients. Notably, patients with high USP11 expression exhibited a lower overall survival rate compared to those with low USP11 expression. Single-cell analysis further revealed predominant expression of the USP11 gene in myeloid-derived suppressor cells within AML patients. Functionally, USP11 promoted cell growth and migration and enhanced chemotherapy-induced EdU incorporation in AML cells. Conversely, siUSP11 suppressed these effects, inhibiting cell growth and migration, as well as chemotherapy-induced EdU incorporation. In a mouse model, USP11 decreases the AML cells' sensitivity to chemotherapy in mice model by chemotherapy. Mechanistically, USP11 upregulated SIRT3 expression and enhanced Reactive Oxygen Species (ROS) production in AML cells under chemotherapy. The proliferative effects of USP11 were attenuated by a SIRT3 Inhibitor, confirming SIRT3 dependency. Additionally, methyltransferase-like 3 (METTL3) was found to enhance USP11 stability through N6-methyladenosine (m6A) RNA modification. Collectively, USP11 promotes chemotherapy resistance in AML cells via a SIRT3/ROS-dependent pathway, playing a pivotal role in treatment-induced drug resistance and emerging as a novel therapeutic target for AML.

Acute myeloid leukemia; Drug resistance; ROS; SIRT3; USP11.