Here we show, using an unbiased functional genomic approach, that FUS‐DDIT3‐expressing mesenchymal stem cells and MLS cell lines are dependent on YAP1, a transcriptional co‐activator and central effector of the Hippo pathway involved in tissue growth and tumorigenesis, and that increased YAP1 activity is a hallmark of human MLS. Here, DDIT3 is linked to McLeod neuroacanthocytosis syndrome.