T-cell acute lymphoblastic leukemias (T-ALL) are aggressive hematological malignancies associated with poor clinical outcome. TP53 alterations (TP53Alt) were rarely identified in TALL at diagnosis and their prognostic impact remains unclear. In a cohort of 476 adults and pediatric T-ALL, TP53Alt were observed in 4% of cases and were associated with chemoresistance and poor prognosis. APR-246, a small compound which restores wild-type configuration to mutated p53, showed efficacy in T-ALL harboring TP53 mutations. More importantly, in TP53 germline T-ALL, Notch1 pathway gain of function mutations were associated with substantial sensitivity to APR-246. Mechanistically, Notch1 activation via p53 downregulation and subsequent ferroptosis induction led to preferential APR-246 sensitivity.
Given that Notch1 pathway oncogenic activation is present in more than 70% of T-ALLs, these observations pave the way for promising perspectives in T-ALL treatment which could benefit from the Achilles heel associated with Notch1 activation sensitizing leukemia cells to APR-246-induced ferroptosis, thus extending the use of APR-246 in T-ALL beyond TP53 alterations.