CRISPR-based genetic screens have revealed essential genes—those required for cellular proliferation and survival—in 14 acute myeloid leukemia (AML) cell lines, according to investigators.
By combining this information with the existing genomic information on these cell lines, the investigators believe they have identified vulnerabilities that could potentially be exploited with new therapies.
The group described their research in Cell.
A major aspect of their study focused on the genes and protein pathways connected to the Ras oncogene, which is the most commonly mutated oncogene in human cancers and plays a role in AML.
“For the most part, the mutant Ras protein itself has been considered to be ‘undruggable,’” said study author Tim Wang, a doctoral student at the Massachusetts Institute of Technology in Cambridge.
“An alternative approach has been to find other genes that Ras-mutant cancers rely on with the hope that one of them may be druggable. Unfortunately, such ‘Ras-synthetic-lethal’ genes have been difficult to identify.”
Using CRISPR-based screens, the investigators were able to gauge the impact of individually knocking out each of the 18,000 protein-coding genes in the human genome.
“This process rapidly enabled us to identify the short list of genes that were selectively required in only the Ras-mutant cells,” explained study author David Sabatini, MD, PhD, of the Massachusetts Institute of Technology.
He and his colleagues found that the enzymes catalyzing the latter steps of the Ras processing pathway, Rce1 and Icmt, displayed synthetic lethality with oncogenic Ras, which suggests they might be therapeutic targets in AML and other cancers driven by oncogenic Ras.
The investigators also said their findings provide further support for the central role of MAPK signaling in Ras-driven cancers, suggest PREX1 and the Rac pathway are critical regulators of MAPK pathway activation, and indicate that c-Raf could be a therapeutic target in cancers driven by oncogenic Ras.
In addition to defining the Ras-specific gene essentiality network, the investigators said they were able to determine the function of previously unstudied genes.
The team started by focusing on genes that were essential in some of the AML cell lines but dispensable for others. For each of these genes, the investigators sifted through their data to find others that showed a matching pattern of essentiality, with the idea that all of them had similar functions.
Indeed, this analysis revealed gene groups that were already known to act together and uncovered novel associations between genes that were not known to be related or had been previously unstudied.
“What’s particularly exciting about this work is that we have just begun to scratch the surface with our method,” Wang concluded. “By applying it broadly, we could reveal a huge amount of information about the functional organization of human genes and their roles in many diseases.”
