Defining function of wild-type and patient specificTP53mutations in a zebrafish model of embryonal rhabdomyosarcoma

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss or gain of functionTP53mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understandingTP53effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-typeTP53, yetTP53mutations when present in tumors are associated with poor prognosis. Employing akRAS^G12D-driven ERMS tumor model and newly generated tp53 null (tp53^-/-) zebrafish, we define both wild-type and patient-specificTP53mutant effects on tumorigenesis. We demonstrate thattp53is a major suppressor of tumor initiation, wheretp53loss expands tumors initiation from <35% to >97% of animals. Next, characterizing three patient-specific mutants finds thatTP53^C176Fpartially retains wild-type p53 apoptotic activity that can be exploited, while theTP53^P153Δand TP53^Y220Cmutants define two structural mutations that predispose to head musculature ERMS.