In healthy bodies, our cells divide in a controlled manner. However, problems arise if our cells begin to divide uncontrollably, growing and spreading unnaturally fast within the body. The buildup of these abnormal cells causes cancer.

Research has led to many different explanations for how certain cancers arise. If certain genes start to behave abnormally, it can cause healthy cells to turn into cancerous, tumour-forming cells. Some genes, called tumor suppressor genes, normally slow down cell division, repair DNA mistakes, or initiate self-destruction of faulty cells. However, when tumor suppressor genes don't work properly, cells can grow out of control, which can cause cancer. A certain gene, called capicua (CIC) has been hypothesized to be one of these tumour suppressor genes. Understanding CIC’s role as a tumour suppressor has proven to be a very difficult task for researchers, as prior to these papers there were very few systems in place to study how removal of CIC may cause cancer in an intact animal.

Both of these papers first address this issue by genetically engineering mice that were programmed to selectively remove CIC when mice reach adulthood. This is necessary because deletion of CIC from younger mice severely impacted the growth and survival of the animals. Upon removing CIC, both groups observed that these mice were dying much younger compared to their normal counterparts. Further research revealed that these knockout mice possessed enlarged thymi, which is the site where certain immune cells, called T cells, mature. This symptom is a key characteristic of T-cell acute lymphoblastic leukemia (T-ALL), which is a form of cancer that specifically affects T-cells. In T-ALL, T-cells fail to finish maturing in the thymus, causing immature T-cells to accumulate and the thymus to enlarge.

After confirming that the knockout mice developed T-ALL, the authors of the Tan paper further characterized the T cell maturation in the thymus of the knockout mice. They found that there was a significant reduction in the number of precursor cells. This shows that T cells were being “held up” in an immature state in the CIC knockout mice.

Finally, both groups wanted to find out what exactly happens to the mice when CIC was removed and how this resulted in the development of T-ALL. CIC regulates the levels of specific genes to prevent uncontrolled cell growth . The Carrasco paper focussed on ETV4, a gene that is controlled by CIC. ETV4 is part of a large family of genes that are involved in controlling cell division, cell maturation, and cell death. They found that ETV4 levels were significantly increased in the absence of CIC. Furthermore, removing ETV4 almost completely nullified the tumour growth of T-ALL that normally arose in the knockout mice! In ⅘ four out of five of the mice tested, removing ETV4 caused no signs of T-ALL by one year of age, a time when normal knockout mice would have already succumbed to the disease. These results strongly indicate that ETV4 is a key mediator of the tumorigenic consequences caused by CIC knockout.

The Tan paper, on the other hand, focussed on MYC, which is a well-known oncogene, meaning it is a gene with the potential to cause cancer if it begins to behave abnormally. The researchers found that the removal of CIC seemed to disrupt the genes that controlled MYC, and as a result they saw an increase in MYC levels. As an increase in MYC levels are correlated with cancer progression, the Tan paper concluded that abnormal levels of MYC may be a driving factor in causing tumour growth in CIC deficient mice.

Altogether, these two papers demonstrate CIC’s role in the development of T-ALL. Further characterization of the mechanism by which CIC causes T-ALL allowed both papers to identify potential genes affected by a knockout of CIC. These studies clearly establish working mouse models for T-ALL and provide mechanistic insight into the tumor suppressor function of CIC.

References:

Tan, Q. et al. Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma. Proc Natl Acad Sci U S A 115, E1511-E1519 (2018). Link to the full text article.

Simon-Carrasco, L. et al. Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma. Genes Dev 31, 1456-1468 (2017). Link to the full text article.