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Significance Despite studies have shown that mutant p53 acquires its GOF by suppressing p63 and p73, the hypothesis has not been tested in vivo and the underlying mechanism is not fully understood. Here, by using mutant p53-R270H knockin andTAp63/p73 -deficient mouse models, we showed that KI mutant p53-R270H antagonizes p63/p73 to shorten mouse life span and to promote T lymphoblastic lymphomagenesis. Mechanistically, we showed that mutant p53 collaborates with the Notch1 intracellular domain (NICD) to abrogate p63/p73-mediated repression of HES1 and ECM1. As a result, HES1 and ECM1 are overexpressed, leading to lymphomagenesis. Thus, we identify a context where mutant p53 contributes to pathogenesis of T lymphoblastic lymphoma by collaborating with the Notch1 pathway to hijack the p63/p73-regulated transcriptional program.

Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1