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

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 Colic, Merve Dede, John G. Doench and Traver Hart ()
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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
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
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
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
Merve Dede: The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences; 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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26867-8

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