TP53 突变 (TP53mut) 发生在 10-20% 的弥漫性大 B 细胞淋巴瘤 (DLBCL) 病例中，是 DLBCL 进展的不利生物标志物。它赋予对免疫化疗、高剂量化疗、自体干细胞移植和抗 CD19 嵌合抗原受体 T 细胞疗法的抵抗力。 TP53mut 的治疗靶向仍然是 DLBCL 治疗中的重大挑战。在此，我们评估了 667 名新诊断 DLBCL 患者的 TP53mut，其中包括 576 名接受免疫化疗利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松 (R-CHOP) 治疗的患者，以及 91 名接受地西他滨联合 R-CHOP 治疗的患者（DR-CHOP、NCT02951728 和 NCT04025593） ）。 TP53mut 独立预测 R-CHOP 治疗的 DLBCL 的预后较差，尽管 DR-CHOP 治疗可以缓解这种情况。基因集富集分析显示，在 TP53mut 患者中，多种病毒调节途径受到抑制，导致免疫调节受到抑制。 TP53mut DLBCL 表现出甲基转移酶 SUV39H1 表达和 H3K9 三甲基化 (H3K9me3) 增加，有助于抑制内源性逆转录病毒 (ERV) 和免疫抑制肿瘤微环境。在 TP53mut DLBCL 细胞系中，地西他滨下调 SUV39H1，抑制 H3K9me3 对 ERV 的占据，并触发 ERV 表达，从而释放干扰素程序和 CD4 T/CD8 T 细胞激活。 SUV39H1 的分子沉默显着消除了地西他滨诱导的 H3K9me3 抑制和 ERV 表达。在TP53mut患者来源的异种移植模型和TP53mut患者中，通过SUV39H1-H3K9me3-ERVs轴联合使用地西他滨和阿霉素的抗肿瘤效果得到改善。总的来说，我们的研究结果强调了 TP53mut DLBCL 中的 ERV 调节电路，以及 ERV 在表观遗传重编程肿瘤微环境以治疗 TP53mut 驱动的癌症中的关键作用。© 2023。四川大学华西医院。

TP53 mutation (TP53mut) occurs in 10-20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53mut remains a significant challenge in DLBCL treatment. Here we assessed TP53mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53mut DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53mut DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53mut patient-derived xenograft models and TP53mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53mut-driven cancers.© 2023. West China Hospital, Sichuan University.