期刊
LEUKEMIA
卷 36, 期 9, 页码 2269-2280出版社
SPRINGERNATURE
DOI: 10.1038/s41375-022-01634-w
关键词
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资金
- National Natural Science Foundation of China [81770213]
- Natural Science Foundation of Tianjin [19JCYBJC26500]
- Clinical Oncology Research Fund of CSCO [Y-XD2019-162, Y-Roche20192-0097]
- National Human Genetic Resources Sharing Service Platform/Cancer Biobank of Tianjin Medical University Cancer Institute and Hospital grant [2005DKA21300]
TP53 mutations are associated with poor prognosis in DLBCL, particularly in GCB and UNC subtypes. APR-246 shows anti-tumor effects by restoring binding of mutant p53 to target genes. Mutations in exons 5, 6, and 7 of TP53 are predictors of progression and survival in DLBCL.
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.
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