Regazzo Giulia, Vari Giulia, Marchesi Francesco, Díaz Méndez Ana Belén, Di Giuliani Marta, Sacconi Andrea, Palombi Francesca, Lulli Valentina, Goeman Frauke, Novello Mariangela, Tomassi Martina, Papa Elena, Bertoni Francesco, Hohaus Stefan, Mengarelli Andrea, Rizzo Maria Giulia
Department of Research, Advanced Diagnostics and Technological Innovation, Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Br J Haematol. 2025 Sep;207(3):802-812. doi: 10.1111/bjh.70017. Epub 2025 Jul 20.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disorder. Prognostic factors include genomic alterations and cell-of-origin (COO) subtypes, even though they cannot fully predict treatment response. MicroRNAs (miRNAs) deregulated in patient tumours and blood are promising non-invasive biomarkers. Several circulating miRNAs were found to be correlated with progression-free survival (PFS), independently of other prognosticators. However, miRNA signatures, rather than individual miRNAs, represent more reliable biomarkers and a better mirror of the disease. In this study, we identified circulating miRNAs differentially expressed between R-CHOP refractory and responding subjects by small-RNA sequencing on serum from 33 DLBCL patients. Among the identified miRNAs, the combined expression of three of them improved the predictive performance and was correlated with PFS. Two out of three miRNAs, miR-421 and miR-324-5p, were also differentially expressed in tumour tissues based on treatment response. Overexpressing these miRNAs reduced cell proliferation, viability and resistance to R-CHOP in the germinal centre B-like COO subtype. EGLN1 and TXNRD1, regulators of oxygen metabolism and redox homeostasis, were identified as miRNA targets and the silencing or inhibition of these genes impaired cell viability and induced ferroptosis. These results support the application of a two-miRNA signature and its targets for novel combined therapeutic interventions in DLBCL.
弥漫性大B细胞淋巴瘤（DLBCL）是一种异质性疾病。预后因素包括基因组改变和细胞起源（COO）亚型，尽管它们不能完全预测治疗反应。在患者肿瘤和血液中失调的微小RNA（miRNA）是很有前景的非侵入性生物标志物。发现几种循环miRNA与无进展生存期（PFS）相关，独立于其他预后因素。然而，miRNA特征，而非单个miRNA，代表更可靠的生物标志物和疾病的更好反映。在本研究中，我们通过对33例DLBCL患者血清进行小RNA测序，鉴定了在R-CHOP难治性和反应性受试者之间差异表达的循环miRNA。在鉴定出的miRNA中，其中三种的联合表达提高了预测性能并与PFS相关。三种miRNA中的两种，即miR-421和miR-324-5p，也基于治疗反应在肿瘤组织中差异表达。过表达这些miRNA可降低生发中心B样COO亚型中的细胞增殖、活力和对R-CHOP的抗性。EGLN1和TXNRD1，氧代谢和氧化还原稳态的调节因子，被鉴定为miRNA靶点，沉默或抑制这些基因会损害细胞活力并诱导铁死亡。这些结果支持应用双miRNA特征及其靶点进行DLBCL的新型联合治疗干预。
