2026-07-22T20:06:09Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/83922024-11-29T17:37:58Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Simón-Carrasco, Lucía author Graña Castro, Osvaldo author Salmón, Marina author Jacob, Harrys K C author Gutierrez, Alejandro author Jiménez, Gerardo author Drosten, Matthias author Barbacid, Mariano author 2017-07-15 CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its role in mammals. CIC is inactivated in a variety of human tumors and has been implicated recently in the promotion of lung metastases. Here, we describe a mouse model in which we inactivated Cic by selectively disabling its DNA-binding activity, a mutation that causes derepression of its target genes. Germline Cic inactivation causes perinatal lethality due to lung differentiation defects. However, its systemic inactivation in adult mice induces T-cell acute lymphoblastic lymphoma (T-ALL), a tumor type known to carry CIC mutations, albeit with low incidence. Cic inactivation in mice induces T-ALL by a mechanism involving derepression of its well-known target, Etv4 Importantly, human T-ALL also relies on ETV4 expression for maintaining its oncogenic phenotype. Moreover, Cic inactivation renders T-ALL insensitive to MEK inhibitors in both mouse and human cell lines. Finally, we show that Ras-induced mouse T-ALL as well as human T-ALL carrying mutations in the RAS/MAPK pathway display a genetic signature indicative of Cic inactivation. These observations illustrate that CIC inactivation plays a key role in this human malignancy. Genes Dev. 2017 ;31(14):1456-1468. 10.1101/gad.300244.117 1549-5477 0890-9369 Genes & development 28827401 http://hdl.handle.net/20.500.12105/8392 CIC Etv4 Ras signaling T-ALL Mouse models Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma