An Essential Gene Dataset Defines Functional Gene Networks

The systematic identification of essential genes, which drive core processes that are required for cancer cell survival and proliferation, can potentially define therapeutic targets for anticancer therapies. To generate an essential gene database for acute myeloid leukemia (AML), Wang and colleagues performed CRISPR/Cas9 gene editing on a panel of 14 genomically characterized AML cell lines. Although the majority of the cell-essential genes identified were implicated in fundamental housekeeping processes necessary for all cells, integrated analysis of genomic and gene essentiality data revealed selective dependence on mutated driver oncogenes present in only subsets of the AML cell lines. Analysis of genes exhibiting differential essentiality between the RAS-dependent and RAS-independent cell lines revealed a restricted set of synthetic lethal interactions with oncogenic RAS that included the guanine nucleotide exchange factor for RAC GTPases, PREX1, and the RAS/MAPK pathway effector genes RAF1 and SHOC2. Similarly, gene essentiality screens performed in isogenic murine Ba/F3 cells differing in Ras dependence also showed that Raf1 and Shoc2, as well as additional MAPK pathway components such as Braf and Rsk, exhibited synthetic lethality with oncogenic RAS. Functional studies revealed that PREX1 is critical for promoting MAPK pathway activation selectively in AML cells in which paralogous RAC-GEFs were not expressed. Correlation analysis of gene essentiality patterns across cell lines identified groups of genes encoding physically interacting proteins, enzymes that function in a common metabolic pathway, TP53 and its negative regulators, as well as novel associations between genes not known to interact and previously uncharacterized genes such as the associations of C1orf27 and C17orf89 with the deUFMylating enzyme UFSP2 and the mitochondrial complex I assembly factor NDUFAF5, respectively. Together, these findings show that the identification of gene essentiality patterns in many cell lines can elucidate the functions of previously uncharacterized genes and identify critical liabilities in cancer.

Wang T, Yu H, Hughes NW, Liu B, Kendirli A, Klein K, et al. Gene essentiality profiling reveals gene networks and synthetic lethal interactions with oncogenic Ras. Cell 2017 Feb 2 [Epub ahead of print].