Discovery of novel tumor suppressors from CRISPR screens reveals lipid-sensitive subtype of AML

CRISPR knockout screens in hundreds of cancer cell lines have revealed a substantial number of context-specific essential genes that, when associated with a biomarker such as lineage or oncogenic mutation, offer candidate tumor-specific vulnerabilities for targeted therapies or novel drug development. Data-driven analysis of knockout fitness screens also yields many other functionally coherent modules that show emergent essentiality or, in some cases, the opposite phenotype of faster proliferation. We develop a systematic approach to classify these suppressors of proliferation, which are highly enriched for tumor suppressor genes, and define a network of 103 genes in 22 discrete modules. One surprising module contains several elements of the glycerolipid biosynthesis pathway and operates exclusively in a subset of AML lines, which we call Fatty Acid Synthesis/Tumor Suppressor (FASTS) cells. Genetic and biochemical validation indicates that these cells operate at the limit of their carrying capacity for saturated fatty acids. Overexpression of saturated acyltransferase GPAT4 or its regulator CHP1 confers a survival advantage in an age-matched cohort of AML patients, indicating the in vitro phenotype reflects a clinically relevant subtype, and suggesting a previously unrecognized risk in clinical trials for fatty acid synthesis pathway inhibitors.