| First Author | Simón-Carrasco L | Year | 2017 |
| Journal | Genes Dev | Volume | 31 |
| Issue | 14 | Pages | 1456-1468 |
| PubMed ID | 28827401 | Mgi Jnum | J:244225 |
| Mgi Id | MGI:5913004 | Doi | 10.1101/gad.300244.117 |
| Citation | Simon-Carrasco L, et al. (2017) Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma. Genes Dev 31(14):1456-1468 |
| abstractText | 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. |
