STAT1 inhibition promotes oxidative stress to sustain leukemia stem cell maintenance.

New strategy to prevent relapse and drug resistance in acute myeloid leukemia (AML) is urgently to be solved. The connection between those properties and leukemia stem cells (LSCs) in AML remains poorly understood. In this study, we demonstrate that leukemia cells with high signal transducer and activator of transcription 1 (STAT1) expression preserve quiescent properties, in contrast, leukemia cells with low STAT1 expression possess active and vulnerable apoptotic properties in AML model, highlighting the differential impact of STAT1 expression on cellular behavior in acute myeloid leukemia. STAT1 depletion damages the quiescence of LSCs and prolongs the survive of AML mice. By inhibiting STAT1 in leukemia cells, we observe a significant elevation in reactive oxygen species (ROS) levels, rendering the cells more susceptible to the detrimental effects of oxidative stress. The synergistic administration of Fludarabine, a potent STAT1 inhibitor, with conventional chemotherapy regimens, augments the efficacy of chemotherapy drugs against AML cells and the sensitivity of LSCs to chemotherapy. In a word, STAT1, as a switch, enables leukemia cells convertible in ROS high and low states. Inhibition of STAT1 enables leukemia cells more sensitive to chemotherapy, STAT1 as a new target offers a promising strategy in AML treatment.