The YAP1-MAML2 fusion drives tumorigenesis and sustains tumor growth.

The Yes1-associated transcriptional regulator-mastermind-like transcriptional co-activator 2 (YAP1-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 YAP1 N-terminal domain interacts with transcriptional enhanced associate domain (TEAD) transcription factors, while the MAML2 C-terminal domain activates YAP1/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 and in xenograft tumor models. This effect was correlated with a downregulation of YAP1/TEAD-driven genes essential for cellular proliferation and survival, as revealed by transcriptomic analysis. Importantly, YM-positive cancer cells were sensitive to YAP1/TEAD-targeted pharmacologic inhibition. Collectively, these findings establish the YM fusion as a critical driver of oncogenesis and a promising therapeutic target for cancers harboring the YM fusion.