Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.

BackgroundAlthough treatment of diffuse large B-cell lymphoma (DLBCL) has progressed considerably in recent years, treatment failure still occurs in about 40% of patients who are refractory/relapse. Recent studies suggest that TP53 mutation may be an important cause of refractory/relapse in DLBCL, but the cause of TP53 mutation remains unclear. MethodsIn the present study, the correlation between TP53 mutation status and APOBEC3A and APOBEC3B expression in DLBCL specimens was searched by detecting the correlation between TP53 mutation and APOBEC3B expression in combination with database informatics analysis. Further, the relationship between APOBEC3B expression and TP53 mutation was analyzed by constructing APOBEC3B induced expression DLBCL cell lines. The effects of APOBEC3B-induced TP53 mutants on DLBCL cell proliferation and drug resistance were also tested. ResultsWe identify APOBEC3B as a critical factor that regulates p53-mutant driven drug resistance of DLBCL. APOBEC3B induces TP53 mutations of DLBCL cells, and its mutation patterns are similar to those in DLBCL patients. Moreover, APOBEC3B-induced p53 mutants promoted growth of DLBCL cells as well as contributed to drug resistance. In human DLBCL, APOBEC3B is aberrantly activated and associated with p53 mutant-mediated refractory/relapsed DLBCL. ConclusionThese findings yield insights into the mechanism of refractory/relapsed DLBCL induced by p53 mutants and reveal APOBEC3B as a new therapeutic target.