GSE168647
Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [ChIP-seq]
Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as a cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells that are also implicated in inflammatory pathways. We identified the immune modulator interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a selective dependency in AML. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene expression studies demonstrated that IRF2BP2 represses IL1B/TNFA signaling via NF-KB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival. Overall design: ChIP-sequencing was performed in parental MV4-11 cells for IRF2BP2, H3K27ac, H3K4me1, H3K4me3, and parental THP1, PDX 16-01, and PDX 17-14 cells for H3K27ac. ChIP-sequencing for HA was performed in THP1, PDX 16-01, PDX 17-14 IRF2BP2-HA cells. ChIP-sequencing for H3K27ac was performed in MV4-11 cells with degradable IRF2BP2 24 hours post degradation of IRF2BP2 with dTAG-13 or untreated control cells. All experiments were controlled with respective input samples. PDX cells from two different patients with AML (PDX 16-01 with CALM-AF10 fusion, PDX 17-14 with MLL-PTD/MLL-AF10 fusion) were used.