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oai:repisalud.isciii.es:20.500.12105/133212025-04-29T10:35:40Zcom_20.500.12105_14556com_20.500.12105_2337com_20.500.12105_2336com_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_14558col_20.500.12105_19616col_20.500.12105_16988

00925njm 22002777a 4500 dc Cervera Mayor, Saint Thomas author Rodriguez-Martin, Carlos author Fernández-Tabanera, Enrique author Melero-Fernández de Mera, Raquel María author Morin, Matias author Fernández-Peñalver, Sergio author Iranzo-Martínez, Maria author Amhih-Cardenas, Jorge author Garcia-Garcia, Laura author Gonzalez-Gonzalez, Laura author Moreno-Pelayo, Miguel Angel author Alonso, Javier author 2021-07-27 Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1-FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1-FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1-FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1-FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1-FLI1 at the cell level should be considered a therapeutic approach to develop in the future. Cancers (Basel) . 2021;13(15):3783. 10.3390/cancers13153783 2072-6694 Cancers 34359682 http://hdl.handle.net/20.500.12105/13321 CRISPR/Cas9 EWSR1–FLI1 Ewing sarcoma Cell cycle arrest Gene therapy. Senescence Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma