TP53 mutations correlate with inferior survival in many cancers. APR-246 is a compound to shift mutant p53 and exhibits anti-cancer effects. Among its effects, APR-246 facilitates the binding of restored p53 mutants to target genes and their transcription. A set of 2464 DLBCL cases from multiple cohorts including our center, was integrated to identify the type and localization of TP53 mutations and clinical impacts. APR-246 was applied in TP53-mutated DLBCL cells and xenograft mouse models to explore the anti-tumor effect. TP53 mutations frequency was 16% and TP53 mutations correlated with poor overall survival (OS) and progression-free survival (PFS) in all cases, especially in germinal center B-cell-like (GCB) and unclassified (UNC) subtypes. Notably, TP53 single mutations in the DNA binding domain (DBD) led to poor OS and PFS. Specifically, mutations in exon 7 correlated with poorer OS, while mutations in exons 5 and 6 associated with inferior PFS. APR-246 induces p53-dependent ferritinophagy of DLBCL cells with TP53 missense mutation on exon 7 and ferroptosis of DLBCL cells harboring wild-type TP53 and other TP53 mutations. TP53 mutations on exons 5, 6 and 7 are predictors of progression and survival. Targeting mutant p53 by APR-246 is a promising therapeutic approach for DLBCL patients.

TP53 突变与许多癌症的低生存率相关。APR-246 是一种转移突变体 p53 的化合物，具有抗癌作用。在其作用中，APR-246 促进恢复的 p53 突变体与靶基因及其转录的结合。整合来自包括我们中心在内的多个队列的一组 2464 例 DLBCL 病例，以确定 TP53 突变的类型和定位以及临床影响。APR-246 应用于 TP53 突变的 DLBCL 细胞和异种移植小鼠模型，以探索其抗肿瘤作用。TP53 突变频率为 16%，在所有病例中，TP53 突变与较差的总生存期 (OS) 和无进展生存期 (PFS) 相关，尤其是在生发中心 B 细胞样 (GCB) 和未分类 (UNC) 亚型中。值得注意的是，DNA 结合域 (DBD) 中的 TP53 单突变导致 OS 和 PFS 较差。具体来说，外显子 7 的突变与较差的 OS 相关，而外显子 5 和 6 的突变与较差的 PFS 相关。APR-246 诱导外显子 7 上具有 TP53 错义突变的 DLBCL 细胞的 p53 依赖性铁蛋白吞噬和携带野生型 TP53 和其他 TP53 突变的 DLBCL 细胞的铁死亡。外显子 5、6 和 7 上的 TP53 突变是进展和生存的预测因子。通过 APR-246 靶向突变体 p53 是 DLBCL 患者的一种有前途的治疗方法。