Simón-Carrasco, LucíaGraña Castro, OsvaldoSalmón, MarinaJacob, Harrys K CGutierrez, AlejandroJiménez, GerardoDrosten, MatthiasBarbacid, Mariano2019-10-012019-10-012017-07-15Genes Dev. 2017 ;31(14):1456-1468.0890-9369http://hdl.handle.net/20.500.12105/8392CIC (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.engVoRCICEtv4Ras signalingT-ALLMouse modelsAdenovirus E1A ProteinsAllelesAnimalsBrain NeoplasmsCell Line, TumorEmbryonic DevelopmentFibroblastsGenes, rasHumansMAP Kinase Signaling SystemMiceMutationOligodendrogliomaPrecursor T-Cell Lymphoblastic Leukemia-LymphomaProto-Oncogene ProteinsProto-Oncogene Proteins c-etsRepressor ProteinsTranscription, GeneticAtribución-NoComercial-CompartirIgual 4.0 Internacional2882740131141456-146810.1101/gad.300244.1171549-5477Genes & developmentopen access