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

Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma.

Author information

1
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
2
Bioinformatics Unit, Structural Biology and Biocomputing Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
3
Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Institut de Biologia Molecular de Barcelona-Consejo Superior de Investigaciones Científicas (CSIC), Parc Cientifíc de Barcelona, 08028 Barcelona, Spain.
5
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08028 Barcelona, Spain.

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:

CIC; Etv4; Ras signaling; T-ALL; mouse models

PMID:
28827401
PMCID:
PMC5588927
DOI:
10.1101/gad.300244.117
[Indexed for MEDLINE]
Free PMC Article

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