Ellegast and colleagues show that monocytic acute myeloid leukemias (AML), enriched in inflammatory and immune gene sets, exploit a transcriptional repressor-namely, IRF2BP2-to mitigate their cell-intrinsic inflammatory output and ensure their maintenance. IRF2BP2 ablation results in heightened inflammatory signals that reach a set point that triggers apoptotic AML cell death in an NF-κB-IL1β-dependent manner. The study identifies IRF2BP2 as a cell-intrinsic vulnerability with potential therapeutic significance in monocytic AML. See related article by Ellegast et al., p. 1760 (6).
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