Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma
- Lucía Simón-Carrasco1,
- Osvaldo Graña2,
- Marina Salmón1,
- Harrys K.C. Jacob1,
- Alejandro Gutierrez3,
- Gerardo Jiménez4,5,
- Matthias Drosten1 and
- Mariano Barbacid1
- 1Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain;
- 2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain;
- 3Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 4Institut de Biologia Molecular de Barcelona-Consejo Superior de Investigaciones Científicas (CSIC), Parc Cientifíc de Barcelona, 08028 Barcelona, Spain;
- 5Institució Catalana de Recerca i Estudis Avançats (ICREA), 08028 Barcelona, Spain
- Corresponding authors: mdrosten{at}cnio.es, mbarbacid{at}cnio.es
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.
Keywords
Footnotes
-
Supplemental material is available for this article.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.300244.117.
- Received April 10, 2017.
- Accepted July 24, 2017.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.