Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts.
Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts.
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DOI：
10.1158/2159-8290.cd-21-0956
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发表时间：
2022-07-06
期刊：
影响因子：
28.2
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中科院分区：
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白血病母细胞是免疫细胞出错。我们假设，炎症通路的失调有助于维持他们的白血病状态，并可作为一种细胞内在的，自我导向的免疫疗法。为此，我们应用全基因组筛选来发现急性髓性白血病（AML）细胞中与炎症通路有关的遗传脆弱性。我们确定了免疫调节剂干扰素调节因子2结合蛋白2（IRF 2BP 2）作为选择性AML依赖。我们验证了AML细胞依赖于IRF 2BP 2的遗传和蛋白质降解的方法在体外和体内遗传。染色质和整体基因表达研究表明，IRF 2BP 2通过NF-κB抑制IL-1 β/TNFα信号传导，IRF 2BP 2扰动导致急性炎症状态，导致AML细胞死亡。这些发现阐明了迄今为止尚未探索的AML依赖性，揭示了细胞内在的炎症信号传导作为引发白血病母细胞进行调节性细胞死亡的机制，并建立了IRF 2BP 2介导的转录抑制作为母细胞存活的机制。
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 implicated in inflammatory pathways. We identified the immune modulator interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a selective AML dependency. 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 IL-1ß/TNFα signaling via NF-κB, 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.