GSE168648
Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [RNA-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: RNA-sequencing was performed in degradable IRF2BP2 MV4-11 and PDX 16-01 cells after 6 hours of dTAG-13 treatment,  and in MV4-11 cells after 24 hours of dTAG-13 treatment. RNA-sequencing was performed on  MV4-11 and PDX 16-01 cells after 6 hours of DMSO treatment and on MV4-11 cells after 24 hours of DMSO treatment. RNA-sequencing was performed in parental PDX cells from eight AML patients.