ELife: Defining function of wild-type and three patient specific TP53 mutations in a zebrafish model of embryonal rhabdomyosarcoma (Ignatius Lab, Houghton Lab, Libich Lab, Chen, Tomlinson)

Jiangfei Chen
Kunal Baxi
Amanda E Lipsitt
Nicole Rae Hensch
Long Wang
Prethish Sreenivas
Paulomi Modi
Xiang Ru Zhao
Antoine Baudin
Daniel G Robledo
Abhik Bandyopadhyay
Aaron Sugalski
Anil K Challa
Dias Kurmashev
Andrea R Gilbert
Gail E Tomlinson
Peter Houghton
Yidong Chen
Madeline N Hayes
Eleanor Y Chen
David S Libich
Myron S Ignatius

Abstract

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from <35% to >97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153D and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153D unexpectedly also predisposes to hedgehog expressing medulloblastomas in the kRASG12D-driven ERMS-model.

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