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LYMPHOMA

APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations

Abstract

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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Fig. 1: Flow chart of data analysis.
Fig. 2: TP53 mutations and prognostic impact in DLBCL.
Fig. 3: Critical gene mutations involved in DLBCL in TP53 WT/MUT subsets in TMUCIH cohort.
Fig. 4: APR-246 represses DLBCL cell proliferation in vitro and in vivo.
Fig. 5: APR-246 induces distinct cell death in DLBCL cells.
Fig. 6: APR-246 induces ROS and lipid peroxidation in DLBCL cells.
Fig. 7: APR-246 induces TP53-dependent ferritinophagy of DLBCL cells with single TP53 missense mutation on exon 7.

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Acknowledgements

The authors thank the Marvel Medical Laboratory, Tianjin Marvelbio Technology Co.,Ltd for providing the assistance for next-generation sequencing.

Funding

This study was supported by National Natural Science Foundation of China grants (81770213), Natural Science Foundation of Tianjin grants (19JCYBJC26500), Clinical Oncology Research Fund of CSCO grants (Y-XD2019-162, Y-Roche20192-0097), and National Human Genetic Resources Sharing Service Platform/Cancer Biobank of Tianjin Medical University Cancer Institute and Hospital grant (2005DKA21300).

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XHW, HLZ, and YHH were responsible for the conception and design of the study. YHH, TYR, and XXW performed the research. XH and HRS performed the PSM and statistical analyses. YHH, TYR, YF, SM, and CS analyzed the data of cell experiments. XL, LFL, LHQ, ZZQ, and SYZ collected the clinic data. YHH wrote the manuscript. XHW and HLZ revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Huilai Zhang or Xianhuo Wang.

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Hong, Y., Ren, T., Wang, X. et al. APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations. Leukemia (2022). https://doi.org/10.1038/s41375-022-01634-w

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