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Chromatin complex dependencies reveal targeting opportunities in leukemia

Author

Listed:
  • Fadi J. Najm

    (Broad Institute of MIT and Harvard)

  • Peter DeWeirdt

    (Broad Institute of MIT and Harvard)

  • Molly M. Moore

    (Broad Institute of MIT and Harvard)

  • Samantha M. Bevill

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Chadi A. El Farran

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Kevin A. Macias

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Mudra Hegde

    (Broad Institute of MIT and Harvard)

  • Amanda L. Waterbury

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Brian B. Liau

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Peter Galen

    (Brigham and Women’s Hospital)

  • John G. Doench

    (Broad Institute of MIT and Harvard)

  • Bradley E. Bernstein

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

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.

Suggested Citation

  • Fadi J. Najm & Peter DeWeirdt & Molly M. Moore & Samantha M. Bevill & Chadi A. El Farran & Kevin A. Macias & Mudra Hegde & Amanda L. Waterbury & Brian B. Liau & Peter Galen & John G. Doench & Bradley , 2023. "Chromatin complex dependencies reveal targeting opportunities in leukemia," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36150-7
    DOI: 10.1038/s41467-023-36150-7
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    References listed on IDEAS

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