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EZH2 deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127261 | GEO | 2020/08/28

REPOSITORIES: GEO

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EZH2 deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress

Project description:Loss-of-function mutations of EZH2, the enzymatic component of PRC2, have been associated with poor outcome and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Using isogenic T-ALL cells, with and without CRISPR/Cas9-induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2 deficient cells exhibited increased sensitivity to structurally diverse inhibitors of CHK1, an interaction that could be validated genetically. 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, as well as in a primary cell model of PRC2 mutant ALL. Mechanistically, EZH2 deficiency resulted in a gene expression signature of immature T-ALL cells, marked transcriptional upregulation of MYCN, increased replication stress, and enhanced dependency on CHK1 for cell survival. Lastly, we demonstrate this phenotype is mediated through de-repression of a distal PRC2-regulated MYCN enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2 mutated T-ALL.

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Calreticulin mutated hematopoietic cells are vulnerable to ATR-CHK1 pathway inhibition

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CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress

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EZH2 deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress

Project description:EZH2 deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress

| PRJNA524626 | ENA

EZH2 deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress

Project description:EZH2 deficient T-cell acute lymphoblastic leukemia is sensitized to CHK1 inhibition through enhanced replication stress

| PRJNA613316 | ENA

Phosphoproteomics analysis of CHK1 inhibitor treatment

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Mis-splicing of mitotic regulators sensitizes SF3B1-mutated human HSCs to CHK1 inhibition [RNA-seq]

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