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Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma
Lucía Simón-Carrasco1, Osvaldo Graña2, Marina Salmón1
1Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, 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.
Insights
CIC inactivation, a transcriptional repressor, drives T-cell acute lymphoblastic lymphoma (T-ALL) in mice by upregulating Etv4. This finding is crucial for understanding human T-ALL and developing targeted therapies.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- Capicua (CIC) is a transcriptional repressor regulated by RAS/MAPK signaling, with its mammalian functions less understood than in Drosophila.
- CIC inactivation is observed in various human tumors and linked to lung metastasis promotion.
- The role of CIC in T-cell acute lymphoblastic lymphoma (T-ALL) is suggested by low-incidence mutations, but its mechanism remains unclear.
Purpose of the Study:
- To investigate the role of CIC inactivation in mammalian cancer, specifically T-ALL.
- To elucidate the molecular mechanisms by which CIC inactivation contributes to T-ALL development.
- To explore the therapeutic implications of CIC inactivation in T-ALL.
Main Methods:
- Generation of a mouse model with selectively disabled DNA-binding activity of CIC.
- Systemic inactivation of CIC in adult mice to induce T-ALL.
- Analysis of target gene derepression, including Etv4.
- Assessment of T-ALL sensitivity to MEK inhibitors in mouse and human cell lines.
- Examination of genetic signatures in Ras-induced and human T-ALL.
Main Results:
- Germline CIC inactivation leads to perinatal lethality due to lung defects.
- Systemic CIC inactivation in adult mice induces T-ALL via Etv4 derepression.
- Human T-ALL relies on ETV4 for its oncogenic phenotype.
- CIC inactivation confers resistance to MEK inhibitors in both mouse and human T-ALL models.
- Ras-induced and human T-ALL with RAS/MAPK pathway mutations show a CIC inactivation signature.
Conclusions:
- CIC inactivation is a key driver of T-ALL in mice and humans.
- ETV4 is a critical downstream effector of CIC in T-ALL pathogenesis.
- CIC inactivation contributes to MEK inhibitor resistance in T-ALL.
- Understanding CIC's role provides insights into T-ALL development and potential therapeutic strategies.
