Publication: Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma
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Publication date
2017-07-15
Authors
Simón-Carrasco, Lucía
Salmón, Marina
Jacob, Harrys K C
Gutierrez, Alejandro
Jiménez, Gerardo
Drosten, Matthias CNIO 
Barbacid, Mariano CNIO
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Cold Spring Harbor Laboratory Press
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Abstract
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.
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Adenovirus E1A Proteins Alleles Animals Brain Neoplasms Cell Line, Tumor Embryonic Development Fibroblasts Genes, ras Humans MAP Kinase Signaling System Mice Mutation Oligodendroglioma Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Proto-Oncogene Proteins Proto-Oncogene Proteins c-ets Repressor Proteins Transcription, Genetic
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Bibliographic citation
Genes Dev. 2017 ;31(14):1456-1468.