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Discovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells

Author

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  • W. Frank Lenoir

    (The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences; The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Micaela Morgado

    (The University of Texas MD Anderson Cancer Center)

  • Peter C. DeWeirdt

    (Broad Institute of MIT and Harvard)

  • Megan McLaughlin

    (The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences; The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Audrey L. Griffith

    (Broad Institute of MIT and Harvard)

  • Annabel K. Sangree

    (Broad Institute of MIT and Harvard)

  • Marissa N. Feeley

    (Broad Institute of MIT and Harvard)

  • Nazanin Esmaeili Anvar

    (The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences; The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Eiru Kim

    (The University of Texas MD Anderson Cancer Center)

  • Lori L. Bertolet

    (The University of Texas MD Anderson Cancer Center)

  • Medina Colic

    (The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences; The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Merve Dede

    (The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences; The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • John G. Doench

    (Broad Institute of MIT and Harvard)

  • Traver Hart

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

Abstract

CRISPR knockout fitness screens in cancer cell lines reveal many genes whose loss of function causes cell death or loss of fitness or, more rarely, the opposite phenotype of faster proliferation. Here we demonstrate a systematic approach to identify these proliferation suppressors, which are highly enriched for tumor suppressor genes, and define a network of 145 such genes in 22 modules. One module contains several elements of the glycerolipid biosynthesis pathway and operates exclusively in a subset of acute myeloid leukemia cell lines. The proliferation suppressor activity of genes involved in the synthesis of saturated fatty acids, coupled with a more severe loss of fitness phenotype for genes in the desaturation pathway, suggests that these cells operate at the limit of their carrying capacity for saturated fatty acids, which we confirm biochemically. Overexpression of this module is associated with a survival advantage in juvenile leukemias, suggesting a clinically relevant subtype.

Suggested Citation

  • W. Frank Lenoir & Micaela Morgado & Peter C. DeWeirdt & Megan McLaughlin & Audrey L. Griffith & Annabel K. Sangree & Marissa N. Feeley & Nazanin Esmaeili Anvar & Eiru Kim & Lori L. Bertolet & Medina C, 2021. "Discovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26867-8
    DOI: 10.1038/s41467-021-26867-8
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    Cited by:

    1. Miquel Anglada-Girotto & Ludovica Ciampi & Sophie Bonnal & Sarah A. Head & Samuel Miravet-Verde & Luis Serrano, 2024. "In silico RNA isoform screening to identify potential cancer driver exons with therapeutic applications," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. 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.
    3. Nazanin Esmaeili Anvar & Chenchu Lin & Xingdi Ma & Lori L. Wilson & Ryan Steger & Annabel K. Sangree & Medina Colic & Sidney H. Wang & John G. Doench & Traver Hart, 2024. "Efficient gene knockout and genetic interaction screening using the in4mer CRISPR/Cas12a multiplex knockout platform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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