Klin Padiatr 2016; 228 - A21
DOI: 10.1055/s-0036-1582498

Targeting mutant TP53 in ALL

S Demir 1, G Selivanova 2, E Tausch 1, L Wiesmüller 1, S Stilgenbauer 1, G te Kronnie 3, KM Debatin 1, LH Meyer 1
  • 1Ulm University Medical Center, Germany
  • 2Karolinska Institute, Sweden
  • 3Padova University, Padova, Italy

Introduction: In ALL, TP53 mutations (TP53mut) are increased at relapse and associated with poor prognosis and resistance. APR-246 binds to mutant p53 and restoring wt conformation.

Methods: TP53mut were analyzed by dHPLC and Sanger sequencing, apoptosis by AnnexinV/PI, p53 targets by western blotting, p53 silencing by lentiviral shRNA, and phosphorylation by phosphoflow cytometry.

Results: APR-246 exposure led to apoptosis in TP53mut ALL and induced functional p53 re-activation indicated by p53Ser15 phosphorylation including expression of downstream targets in a p53 dependent manner in TP53mut but not TP53wt ALL. Additionally, APR-246 re-sensitized TP53mut resistant leukemias strongly synergizing with the DNA-damage inducer doxorubicin.

Conclusion: APR-246 functionally re-activates mutant p53, leading to apoptosis induction and re-sensitization of TP53mut but not TP53wt ALL cells. Thus, targeting mutated p53 provides a promising novel strategy in this high-risk subtype of ALL.