The YAP1-MAML2 fusion drives tumorigenesis and sustains tumor growth

The Yes!-associated transcriptional regulator-mastermind-like transcriptional co-activator 2 (YAP!-MAML2 [YM]) fusion protein arises from an intrachromosomal inversion and is implicated in various cancers. However, the oncogenic role of the endogenous YM fusion protein remained undefined. In this study, we employed YM-positive ES-2 ovarian cancer cells as a model to explore the roles of the YM fusion in cancer initiation and maintenance. The YM fusion protein localizes to nuclear speckles and contains bifunctional domains: the YAP! N-terminal domain interacts with transcriptional enhanced associate domain (TEAD) transcription factors, while the MAML2 C-terminal domain activates YAP!/TEAD-driven transcription. YM exhibited transforming activity, as shown by its ability to induce focus formation in immortalized epithelial cells. YM depletion reduced cancer cell proliferation and survival both in vitro and in xenograft tumor models. This effect was correlated with a downregulation of YAP!/TEADdriven genes essential for cellular proliferation and survival, as revealed by transcriptomic analysis. Importantly, YM-positive cancer cells were sensitive to YAP!/TEAD-targeted pharmacologic inhibition. Collectively, these fi ndings establish the YM fusion as a critical driver of oncogenesis and a promising therapeutic target for cancers harboring the YM fusion.