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

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 , little is known about its role in mammals. 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 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 mutations, albeit with low incidence. inactivation in mice induces T-ALL by a mechanism involving derepression of its well-known target, Importantly, human T-ALL also relies on ETV4 expression for maintaining its oncogenic phenotype. Moreover, 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.

A double‐edged sword: The world according to Capicua in cancer

“…In mutants, Etv4 repression by CIC is cancelled, resulting in upregulation of Mmp9 and aberration of ECM remodeling . The conditional Cic mutation lacking exons 2–6 also induced abnormal lung alveolarization with reduced alveolar surfactant protein expression . Moreover, hematopoietic lineage cell‐specific knockout of Cic induced remarkable autoimmune responses with increased follicular helper T cells, which was mediated by derepression of Etv5 …”

“…Interestingly, a glial fibrillary acidic protein‐Cre‐induced Cic mutation in mouse failed to induce oligodendroglioma . Instead, when the same mutation was ubiquitously induced in adult mice, T‐cell lymphoblastic leukemia developed at high penetrance.…”

“…Interestingly, a glial fibrillary acidic protein-Cre-induced Cic mutation in mouse failed to induce oligodendroglioma. (24) Instead, when the same mutation was ubiquitously induced in adult mice, T-cell lymphoblastic leukemia developed at high penetrance. Although the result might be caused by the difference in genetic predisposition for cancer between human and mouse, it was consistent with the fact that mutations of CIC as well as the RTK/RAS/MAPK pathway genes were reported in human T-ALL (Table 1).…”

“…Although the result might be caused by the difference in genetic predisposition for cancer between human and mouse, it was consistent with the fact that mutations of CIC as well as the RTK/RAS/MAPK pathway genes were reported in human T-ALL (Table 1). (24,44) CIC fusion genes in human cancer. CIC is also involved in human malignancies as gene fusions associated with chromosomal translocation involving 19q13.…”

Multi-omic analysis of CIC’s functional networks reveals novel interaction partners and a potential role in mitotic fidelity

“…Capicua (CIC) is a transcriptional repressor that is mutated or rearranged in in several cancer types, including undifferentiated small round cell sarcomas 1 (~60% frequency), oligodendrogliomas 2,3 (~50-80%), gastric adenocarcinomas 4 (~9%), endometrial carcinomas 5 (~7%), and melanomas (~8%) 6,7 . CIC loss has also been implicated in prostate cancer 8 , lung cancer 9 , and T-cell lymphoblastic leukemia/lymphoma 10,11 . CIC alterations and/or loss of CIC activity have been associated with inferior outcomes [12][13][14][15] and with aggressive phenotypes such as increased metastatic ability 9 and resistance to MAPK inhibitors 16,17 , indicating that CIC likely functions as a tumour suppressor.…”