Reference

Genes Dev. 2017 Jul 15;31(14):1456-1468. doi: 10.1101/gad.300244.117. Epub 2017 Aug 21. GD Cover Small

Authors

Simón-Carrasco L, Graña O, Salmón M, Jacob HKC, Gutierrez A, Jiménez G, Drosten M, Barbacid M.

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.

 

Description

CIC (también conocido como Capicua) es un represor transcripcional negativamente regulado por la vía de Ras/MAPK. En este trabajo demostramos que su inactivación en ratones en línea germinal produce la muerte de los neonatos. Sin embargo, su inactivación en adultos induce el desarrollo de linfoma linfoblástico de células T y proporciona resistencia a inhibidores de la vía MAPK. Finalmente, hemos encontrado que hasta un 10% de los pacientes humanos con T-ALL albergan mutaciones en CIC.

 

 

Grupodic

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de “Oncología experimental” dirigido por Mariano Barbacid en el CNIO investiga los mecanismos implicados en el desarrollo de tumores prestando especial atención a aquellos inducidos por el oncogén KRAS y sus efectores. Utilizando modelos de ratón, buscan y validan dianas terapéuticas con el objetivo de establecer una combinación racional de terapias que puedan proporcionar un beneficio terapéutico significativo en la clínica.

 

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