Chromatin complex dependencies reveal targeting opportunities in leukemia

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Chromatin regulators are frequently altered in human cancers, presenting potential therapeutic targets.
• These regulators function within multi-subunit complexes, suggesting complex-level dependencies in cancer.

Purpose of the Study:

• To investigate functional relationships among chromatin regulators using combinatorial CRISPR screening.
• To identify novel gene-gene interactions and potential therapeutic targets within chromatin regulator complexes.

Main Methods:

• Utilized a large-scale combinatorial CRISPR knockout screen testing over 35,000 gene-pair interactions in leukemia cells.
• Employed a library of over 300,000 constructs for comprehensive genetic perturbation.

Main Results:

• Identified gene pairs with compensatory non-lethal or synergistic lethal interactions, enriching for paralogs and members of the same protein complex.
• Highlighted dependencies within complexes such as MCM histone exchange, NuRD, and HBO1 (KAT7) complex, which were not evident from single knockout screens.
• Discovered synergistic lethality in KAT7 complex member combinations, specifically implicating the ING5 PHD domain as a potential therapeutic target.

Conclusions:

• Combinatorial screening is a powerful method for uncovering mechanistic insights into complex biological networks.
• This approach effectively identifies novel therapeutic targets within the redundant networks of chromatin regulators in cancer.