posted on 2023-04-03, 22:22authored byTheresa E. León, Tanya Rapoz-D'Silva, Cosetta Bertoli, Sunniyat Rahman, Michael Magnussen, Brian Philip, Nadine Farah, Simon E. Richardson, Sara Ahrabi, José Afonso Guerra-Assunção, Rajeev Gupta, Elisabeth P. Nacheva, Stephen Henderson, Javier Herrero, David C. Linch, Robertus A.M. de Bruin, Marc R. Mansour
Supplementary information provided in this work.
Funding
Blood Cancer UK
Freemason's Grand Charity
Hospital Saturday Fund
UCL/UCLH Biomedical Research Centre
Cancer Research UK
The Prince Fund
Carol's Smile Charity
Great Ormond Street Hospital Children's Charity
Hardy Keinan Fellowship
UK NIHR Clinical Lectureship
CRUK
MRC-UCL University
Blood Cancer UK Bennett Fellowship
History
ARTICLE ABSTRACT
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. Finally, we demonstrate this phenotype is mediated through derepression of a distal PRC2-regulated MYCN enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2-mutated T-ALL.
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.This article is highlighted in the In This Issue feature, p. 890