EZH2 -Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Loss-of-function mutations of , 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...

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Bibliographic Details
Published in:Cancer discovery 2020-07, Vol.10 (7), p.998-1017
Main Authors: León, Theresa E, Rapoz-D'Silva, Tanya, Bertoli, Cosetta, Rahman, Sunniyat, Magnussen, Michael, Philip, Brian, Farah, Nadine, Richardson, Simon E, Ahrabi, Sara, Guerra-Assunção, José Afonso, Gupta, Rajeev, Nacheva, Elisabeth P, Henderson, Stephen, Herrero, Javier, Linch, David C, de Bruin, Robertus A M, Mansour, Marc R
Format: Article
Language:English
Subjects:
Cell Proliferation
Checkpoint Kinase 1 - metabolism
Enhancer of Zeste Homolog 2 Protein - metabolism
Humans
Mutation
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
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Summary:Loss-of-function mutations of , 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 , 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 , increased replication stress, and enhanced dependency on CHK1 for cell survival. Finally, we demonstrate this phenotype is mediated through derepression of a distal PRC2-regulated enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2-mutated T-ALL. SIGNIFICANCE: Loss-of-function mutations of PRC2 genes are associated with chemotherapy resistance in T-ALL, yet no specific therapy for this aggressive subtype is currently clinically available. Our work demonstrates that loss of EZH2 activity leads to MYCN-driven replication stress, resulting in increased sensitivity to CHK1 inhibition, a finding with immediate clinical relevance. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-19-0789