APR‐246 TRIGGERS FERRITINOPHAGY AND FERROPTOSIS OF DIFFUSE LARGE B‐CELL LYMPHOMA CELLS WITH DISTINCT TP53 MUTATIONS

Purpose: Recently, seven diffuse large B-cell lymphoma (DLBCL) genotypes were defined, among which the A53 type showed adverse outcomes. Thus, it is necessary to explore promising anticancer drugs and therapies for TP53 dysfunction patients. APR-246 a compound combat mutant p53 in solid hematological tumors, but effect of on DLBCL remains unclear. Methods: A set 2464 cases from multiple cohorts including our center, was integrated identify localization mutations clinical impacts. applied TP53-mutated cells xenograft mouse models anti-tumor underlying mechanism. Results: Of all patients, 16% contained mutations. correlated with poor overall survival (OS) progression-free (PFS) cases. Notably, TP53single DBD (exons 5-8) resulted OS PFS, those exons (3-4, 9-11) outside DBD. carrying 5 7 or intact more sensitivity than containing spliced null TP53. knocked-out less APR-246. also significantly inhibited tumor growth animal model. The decreased cell viability induced by almost completely rescued either iron chelater deferoxamine (DFO) ferrostatin-1 (Fer-1), indicating that ferroptosis mediates death. APR-246-induced death an action involving ROS production, not altered knockout OCI-LY7. However, only OCI-LY3, TMD8 TP53-knockout OCI-LY7 cells, autophagy TP53-dependent. Further, re-expressing wild-type similar response as OCI-LY3 harboring APR-246, while re-expressed expression ALOX5, ALOX12, ALOX15 increased after treatment 24 h. LC3-II level enhanced substrate SQSTM1 reduced treatment, confirming induces cells. Additionally, FTH1, NCOA4 HERC2 examined data demonstrated had no these proteins, restored involved ferritinophagy These findings further confirmed TP53-KO p53. Keywords: Aggressive non-Hodgkin lymphoma, Diagnostic Prognostic Biomarkers, Genomics, Epigenomics, Other -Omics No conflicts interests pertinent abstract.