CRISPR/Cas9 gene editing tools are one of the most promising methods for advancing the treatment of genetic diseases including cancer, and this research field is making continuous progress. Now, in a new study, Dr. Sandra Rodríguez-Perales of the Spanish National Cancer Research Center (CNIO) and his research team have made new progress: using this technology to eliminate the so-called fusion gene, which guides the development of cancer therapies that specifically destroy tumors without affecting healthy cells in the future.
Fusion genes are an abnormal result of incorrectly ligating DNA fragments from two different genes, which is an accidental event during cell division. If the cells cannot benefit from this error, they will die and the fusion gene will be eliminated. But when this error leads to reproductive or survival advantages, cells carrying this fusion gene will proliferate, and the fusion gene and the protein it encodes will trigger tumor formation.
Rodríguez-Perales explained that “many chromosomal rearrangements and the resulting fusion genes are the origin of childhood sarcomas and leukemia.” Fusion genes have also been found in other cancers such as prostate tumors, breast cancer, lung tumors and brain tumors. In total, they are present in up to 20% of cancers.
Since fusion genes only exist in tumor cells, they have attracted great interest from the scientific community because they are highly specific therapeutic targets, attacking them will only affect tumors but not healthy cells, this is where the CRISPR/Cas9 technology takes effect. Through this technology, people can target specific sequences of the genome, just like using molecular scissors to cut and paste DNA fragments, thereby modifying the genome in a controlled way. In this new study, the Rodríguez-Perales team used CRISPR/Cas9 to remove tumor-causing fusion genes in cell lines and mouse models of Ewing’s sarcoma and chronic myelogenous leukemia (CML), thereby successfully eliminating tumor cells.
This is the first time that CRISPR/Cas9 has been successfully applied to selectively eliminate fusion genes in tumor cells. Early strategies of other research teams were based on modifying the connection between the two genes involved in the fusion and introducing DNA sequences that induce cell death. The problem is that the introduction of foreign sequences proved to be ineffective in eliminating tumors.
The Rodríguez-Perales team used a completely different method to induce tumor cells to self-destruct. Raúl Torres-Ruiz explains, “Our strategy is to make two cuts in the introns (non-coding regions of the gene) located at the ends of the fusion gene. In this way, in the process of trying to repair these cuts on its own, the tumor cells will connect the two ends of the cut, which will cause the fusion gene in the middle to be completely eliminated. Because this fusion gene is vital to the survival of tumor cells, this repair will automatically lead to their death.”
Rodríguez-Perales continued, “Our next step will be to conduct more research to analyze the safety and efficiency of our method.” He concluded, “These steps are critical to understanding whether our method can be transformed into a potential clinical treatment in the future. In addition, we will investigate whether our strategy (which we have observed to work in Ewing`s sarcoma and chronic myeloid leukemia) is also effective for other cancers caused by fusion genes for which there is currently no effective treatment.”
