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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Lacy SE, Barrans SL, Beer PA, Painter D, Smith AG, Roman E, et al. Targeted sequencing in DLBCL, molecular subtypes, and outcomes: A Haematological Malignancy Research Network report. Blood 2020;135:1759–71.
Sehn LH, Salles G. Diffuse large B-Cell lymphoma. N Engl J Med. 2021;384:842–58.
Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018;378:1396–407.
Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24:679–90.
Wright GW, Huang DW, Phelan JD, Coulibaly ZA, Roulland S, Young RM, et al. A probabilistic classification tool for genetic subtypes of diffuse Large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37:551–68.e14.
Laptenko O, Prives C. Transcriptional regulation by p53: One protein, many possibilities. Cell Death Differ. 2006;13:951–61.
Kastenhuber ER, Lowe SW. Putting p53 in context. Cell 2017;170:1062–78.
Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43:830–7.
Bykov VJN, Eriksson SE, Bianchi J, Wiman KG. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 2018;18:89–102.
Brosh R, Rotter V. When mutants gain new powers: News from the mutant p53 field. Nat Rev Cancer. 2009;9:701–13.
Aschauer L, Muller PA. Novel targets and interaction partners of mutant p53 gain-of-function. Biochem Soc Trans. 2016;44:460–6.
Hemann MT, Fridman JS, Zilfou JT, Hernando E, Paddison PJ, Cordon-Cardo C, et al. An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo. Nat Genet. 2003;33:396–400.
Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 2002;8:282–8.
Zhang Q, Bykov VJN, Wiman KG, Zawacka-Pankau J. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 2018;9:439.
Sobhani M, Abdi J, Manujendra SN, Chen C, Chang H. PRIMA-1Met induces apoptosis in Waldenström’s Macroglobulinemia cells independent of p53. Cancer Biol Ther. 2015;16:799–806.
Birsen R, Larrue C, Decroocq J, Johnson N, Guiraud N, Gotanegre M, et al. APR-246 induces early cell death by ferroptosis in acute myeloid leukemia. Haematologica. 2022;107:403–16.
Maslah N, Salomao N, Drevon L, Verger E, Partouche N, Ly P, et al. Synergistic effects of PRIMA-1(Met) (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica 2020;105:1539–51.
Mohell N, Alfredsson J, Fransson Å, Uustalu M, Byström S, Gullbo J, et al. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death Dis. 2015;6:e1794.
Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res. 2011;17:2830–41.
Tessoulin B, Descamps G, Moreau P, Maïga S, Lodé L, Godon C, et al. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood 2014;124:1626–36.
Lehmann S, Bykov VJ, Ali D, Andrén O, Cherif H, Tidefelt U, et al. Targeting p53 in vivo: A first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30:3633–9.
Sallman DA, DeZern AE, Garcia-Manero G, Steensma DP, Roboz GJ, Sekeres MA, et al. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. J Clin Oncol. 2021;39:1584–94.
Dubois S, Viailly PJ, Bohers E, Bertrand P, Ruminy P, Marchand V, et al. Biological and clinical relevance of associated genomic alterations in MYD88 L265P and non-L265P-mutated diffuse large B-Cell lymphoma: Analysis of 361 cases. Clin Cancer Res. 2017;23:2232–44.
Sha C, Barrans S, Cucco F, Bentley MA, Care MA, Cummin T, et al. Molecular high-grade B-Cell lymphoma: Defining a poor-risk group that requires different approaches to therapy. J Clin Oncol. 2019;37:202–12.
Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell 2017;171:481–94.e15.
Young KH, Leroy K, Møller MB, Colleoni GW, Sánchez-Beato M, Kerbauy FR, et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 2008;112:3088–98.
Miao Y, Medeiros LJ, Li Y, Li J, Young KH. Genetic alterations and their clinical implications in DLBCL. Nat Rev Clin Oncol. 2019;16:634–52.
Challa-Malladi M, Lieu YK, Califano O, Holmes AB, Bhagat G, Murty VV, et al. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell. 2011;20:728–40.
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: Process and function. Cell Death Differ. 2016;23:369–79.
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012;148:213–27.
Rathkey JK, Zhao J, Liu Z, Chen Y, Yang J, Kondolf HC, et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol. 2018;3:eaat2738.
Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12:1–222.
Caserta TM, Smith AN, Gultice AD, Reedy MA, Brown TL. Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties. Apoptosis 2003;8:345–52.
Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76.
Scherz-Shouval R, Elazar Z. Regulation of autophagy by ROS: Physiology and pathology. Trends Biochem Sci. 2011;36:30–8.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060–72.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017;171:273–85.
Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharm Ther. 2014;141:150–9.
Chen X, Yu C, Kang R, Kroemer G, Tang D. Cellular degradation systems in ferroptosis. Cell Death Differ. 2021;28:1135–48.
Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 2020;30:3411–23.e7.
Chu B, Kon N, Chen D, Li T, Liu T, Jiang L, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol. 2019;21:579–91.
Hilton RJ, David Andros N, Watt RK. The ferroxidase center is essential for ferritin iron loading in the presence of phosphate and minimizes side reactions that form Fe(III)-phosphate colloids. Biometals 2012;25:259–73.
Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016;12:1425–8.
Fuhrmann DC, Mondorf A, Beifuß J, Jung M, Brüne B. Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis. Redox Biol. 2020;36:101670.
Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32.
Mancias JD, Pontano Vaites L, Nissim S, Biancur DE, Kim AJ, Wang X, et al. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife. 2015;4:e10308.
Peller S, Rotter V. TP53 in hematological cancer: Low incidence of mutations with significant clinical relevance. Hum Mutat. 2003;21:277–84.
Young KH, Weisenburger DD, Dave BJ, Smith L, Sanger W, Iqbal J, et al. Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAILreceptor-2, predict for poor survival in diffuse large B-cell lymphoma. Blood 2007;110:4396–405.
Deneberg S, Cherif H, Lazarevic V, Andersson PO, von Euler M, Juliusson G. et al. An open-label phase I dose-finding study of APR-246 in hematological malignancies. Blood Cancer J. 2016;6:e447
Saha MN, Jiang H, Yang Y, Reece D, Chang H. PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa. Mol Cancer Ther. 2013;12:2331–41.
The authors thank the Marvel Medical Laboratory, Tianjin Marvelbio Technology Co.,Ltd for providing the assistance for next-generation sequencing.
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).
The authors declare no competing interests.
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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