Chromatin complex dependencies reveal targeting opportunities in leukemia.
Fadi J NajmPeter C DeWeirdtMolly M MooreSamantha M BevillChadi A El FarranKevin A MaciasMudra HegdeAmanda L WaterburyBrian B LiauPeter van GalenJohn G DoenchBradley E BernsteinPublished in: Nature communications (2023)
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.
Keyphrases
- genome wide
- transcription factor
- dna damage
- high throughput
- emergency department
- cancer therapy
- computed tomography
- magnetic resonance imaging
- dna methylation
- climate change
- drug delivery
- cell death
- magnetic resonance
- cell proliferation
- young adults
- cell cycle arrest
- protein protein
- human health
- wild type
- diffusion weighted imaging