STING is crucial for the survival of AML1-ETO leukemia cells
Even though acute myeloid leukemia (AML) patients with a RUNX1::RUNX1T1 (AE) fusion have a relatively favorable prognosis, approximately 50% relapse within 2.5 years and develop resistance to subsequent chemotherapy1. It is therefore imperative to identify novel therapeutic targets for AE leukemia to improve outcomes. In this study, we unveil that targeting STING effectively suppresses the growth of AE leukemia cells. Both genetic and pharmacological inhibition of STING lead to the diminish of AE leukemia cells. Importantly, in a mouse primary AE leukemia model, STING deletion significantly attenuates leukemogenesis and prolongs the animals' lifespan. Blocking the downstream inflammatory pathway of STING yields similar effects to STING inhibition in AE leukemia cells, highlighting the pivotal role of STING-dependent inflammatory responses in sustaining the survival of AE leukemia cells. Moreover, through a genome-wide CRISPR screen, we identified fatty acid desaturase 2 (FADS2) as a non-canonical factor downstream of STING inhibition that mediates cell death. Inhibition of STING releases FADS2 activity, consequently inducing the synthesis of polyunsaturated fatty acids (PUFAs) and triggering lipid peroxidation-associated cell death2. Taken together, these findings reveal a critical function of STING in the survival of AE-positive AML cells and suggest STING to be a potential therapeutic target for clinical intervention in these patients. Overall design: To gain insights into the molecular mechanism of STING inhibition in AE leukemia cells,we performed Switching Mechanism at the 5' end of the RNA Transcript sequencing (SMART-Seq) to analyze the mRNA profiles of WT and AE9a c-Kit+ cells treated with DMSO or C-176