Inhibition of PLK4 remodels histone methylation and activates immune response via cGAS-STING pathway in TP53 mutated AML.

Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53 mutated AML, we identified polo-like kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms and therapeutic potential in TP53 mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wildtype AML and was increased in TP53 mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wildtype AML. Prolonged PLK4 inhibition suppressed the growth of TP53 mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wildtype and mutated AML, resulting in histone modification through PLK4 induced PRMT5 phosphorylation. In TP53 mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon co-culture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53 mutated AML.