TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells

Genetic alterations have been reported for decades in most human embryonic stem cells (hESCs). Survival advantage, a typical trait acquired during long-term in vitro culture, results from the induction of BCL2L1 upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest candidates associated with genetic alterations that occur via escape from mitotic stress. However, the underlying mechanisms for BCL2L1 induction remain unknown. Furthermore, abnormal mitosis and the survival advantage that frequently occur in late passage are associated with the expression of BCL2L1, which is in locus 20q11.21. In this study, we demonstrated that the expression of TPX2, a gene located in 20q11.21, led to BCL2L1 induction and consequent survival traits under mitotic stress in isogenic pairs of hESCs and human induced pluripotent stem cells (iPSCs) with normal and 20q11.21 CNVs. High Aurora A kinase activity by TPX2 stabilized the YAP1 protein to induce YAP1-dependent BCL2L1 expression. A chemical inhibitor of Aurora A kinase and knockdown of YAP/TAZ significantly abrogated the high tolerance to mitotic stress through BCL2L1 suppression. These results suggest that the collective expression of TPX2 and BCL2L1 from CNV at loci 20q11.21 and a consequent increase in YAP1 signaling promote genome instability during long-term in vitro hESC culture. New details of the molecular mechanisms behind problematic genetic aberrations that can affect cultured human embryonic stem cells could help efforts to maintain stable cell lines that hold great promise for treating a wide variety of diseases. Researchers in South Korea led by Hyuk-Jin Cha at Seoul National University investigated abnormalities in stem cell control systems leading to a condition known as survival advantage, which can allow abnormal cells to proliferate. They identified a gene (TPX2) whose expression activates another gene already known to be involved in triggering the survival advantage process. Their research further revealed that the protein encoded by TPX2 achieves this effect indirectly, by interacting with another protein known to be able to control the activity of specific genes. Revealing this molecular signaling chain could assist culture of stable stem cells.