GSE127261
EZH2 deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress
Loss-of-function mutations of EZH2, the enzymatic component of PRC2, are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) and have been associated with chemotherapy resistance and poor outcome. Using isogenic T-ALL cells, with and without CRISPR-induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2 deficient cells exhibited increased sensitivity to structurally diverse CHK1 inhibitors, an interaction that could be validated genetically. Notably, EZH2 deficient cells acquired a gene expression signature of immature T-ALL cells, with significant enrichment of MYC target genes. Mechanistically, EZH2 deficiency was associated with marked transcriptional upregulation of MYCN, increased replication stress, and enhanced dependency on CHK1 for cell survival. Furthermore, small molecule inhibition of CHK1 had efficacy in delaying tumor progression in isogenic EZH2 deficient, but not EZH2 wild-type T-ALL cells in vivo, suggesting there is an exploitable therapeutic window for CHK1 inhibitors in high risk EZH2 mutated T-ALL. Overall design: Jurkat EZH2-WT (biological triplicates) versus Jurkat CRISPR/Cas9- edited -EZH2-KO1 (biological triplicates) and -EZH2-KO2 (biological triplicates) cell lines are analysed by RNA-seq