Chromatin complex dependencies reveal targeting opportunities in leukemia

• Published in: Nature communications 2023-01, Vol.14 (1), p.448-10, Article 448
• Main Authors: Najm, Fadi J., DeWeirdt, Peter, Moore, Molly M., Bevill, Samantha M., El Farran, Chadi A., Macias, Kevin A., Hegde, Mudra, Waterbury, Amanda L., Liau, Brian B., van Galen, Peter, Doench, John G., Bernstein, Bradley E.
• Format: Article
• Language: English
• Subjects: 13/106; 38/39; 38/91; 45/47; 631/208/191; 631/67/1990/283; 631/67/69; Chromatin; Chromatin - genetics; Chromatin Assembly and Disassembly; Combinatorial analysis; CRISPR; Epigenetics; Histone Acetyltransferases - metabolism; Histone deacetylase; Histones; Humanities and Social Sciences; Humans; Inactivation; Lethality; Leukemia; Leukemia - drug therapy; Leukemia - genetics; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; multidisciplinary; NuRD protein; Proteins; Science; Science (multidisciplinary); Target recognition; Therapeutic applications; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36150-7

Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks. Epigenetic regulators are potential therapeutic drug targets in leukemia. Here, the authors perform combinatorial CRISPR knockouts to test gene-gene pairings in leukemia cells to discover compensatory non-lethal or synergistic lethal combinations with therapeutic potential.