Leveraging CRISPR/Cas9 to target fusion oncogenes in vivo for selective elimination of cancer cells

Fusion oncogenes are strong driven factor for tumor progress, which only express in cancer cell. Researchers observed that eliminating directionally fusion oncogenes where the cancer induced by that, giving rise to apoptosis of cancer cells. Though this therapeutic target is very potential, directional killing specific cell is more challenging. For conquering the critical problem, the researchers devised a simple, efficient, and non-patient-specific gene-editing strategy, based on CRISPR/Cas9 technology, that is able to specifically destroy fused oncogenes in cancer cells by targeting the two introns involved in the rearrangement. The study was published in Nature Communications with the heading: "In Vivo CRISPR/Cas9 targeting of Fusion Oncogenes for Selective Elimination of Cancer Cells [1]."

 

What is fusion oncogene?

Fusion gene refers to a chimera that connects the coding regions of two or more genes end to end and puts them under the control of the same set of regulatory sequences including promoters, enhancers, ribosome binding sequences, terminator, etc. That is an abnormal result of incorrect connection of DNA fragment from two different genes, the accidental circumstance during cell division. Fusion gene and its encoding protein, like transcription factor or tyrosine kinase, will trigger cell uncontrolled proliferation and tumorigenesis. At present, people have found that fusion genes are widely present in nearly 20% of cancer types such as prostate tumor, breast cancer, lung tumor, and brain tumor.

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Selective elimination of tumor cells by CRISPR/Cas9

After a series of attempts, researchers have developed a targeted fusion oncogene editing method based on CRISPR/Cas9 technology, and conducted on the EWSR1-FLI1 fusion gene. This method targets two intron sequences of fusion oncogenes, which can induce cancer cell-specific genome deletions, thereby eliminating key protein domains or changing the reading frame of the fusion oncogene. It is worth noting that this CRISPR/Cas9-based method only induces deletions in cells containing fusion oncogenes, but does not affect the exon sequence or the protein expression of the germline non-rearranged alleles. The same two guide RNA (sgRNAs) allow specific breakpoints of different subtypes of or specific fusion oncogenes for each patient, so it is a versatile method for treating cancer-related fusion oncogenes.

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Reference:

[1] Martinez-Lage, M et al. “In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells.” Nature communications vol. 11,1 5060. 8 Oct. 2020, doi:10.1038/s41467-020-18875-x


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