Verdú-Bou Miriam, Baptista Maria Joao, Ribeiro Marcelo Lima, Méndez-López Aleix, Profitós-Pelejà Núria, Frontzek Fabian, Roué Gaël, Mate José Luís, Pellicer Mireia, Abrisqueta Pau, Castellví Josep, Bastos-Oreiro Mariana, Menárguez Javier, Alcoceba Miguel, González-Barca Eva, Climent Fina, Salar Antonio, Sancho Juan-Manuel, Staiger Annette M, Ott German, Anagnostopoulos Ioannis, Esteller Manel, Lenz Georg, Tapia Gustavo, Navarro José-Tomás
Department of Medicine, Universitat Autònoma de Barcelona, Badalona, Spain.
Lymphoid Neoplasms Group, Josep Carreras Leukaemia Research Institute, Badalona, Spain.
Blood Adv. 2025 Jun 24;9(12):2953-2967. doi: 10.1182/bloodadvances.2025016180.
Plasmablastic lymphoma (PBL) is an uncommon and aggressive B-cell lymphoma with a poor prognosis. Some studies have described genetic alterations in PBL, but its transcriptome has been scarcely studied, and molecular mechanisms driving lymphomagenesis remain poorly understood. Our goal was to delineate transcriptomic profiles to identify potential biomarkers for novel targeted therapy in PBL. RNA sequencing uncovered an enrichment of cell cycle-related genes, including MYC and E2F targets, and genes involved in G2/M checkpoint in PBL. Microarray analyses discovered 2 microRNA expression signatures depending on the presence of MYC translocation. Interestingly, miR-150-5p was downregulated, whereas E2F3 and BIRC5 (survivin), a cell cycle activator and an antiapoptotic regulator, respectively, were upregulated. Increasing miR-150-5p in PBL-1 cells induced G1 cell cycle arrest, suppressed proliferation by transcriptionally repressing E2F3, and promoted apoptosis by the downregulation of BIRC5. Interestingly, the miR-150-5p tumor suppressor activity was diminished in E2F3-knockdown cells. The combined inhibition of E2F3 and survivin attenuated lymphomagenesis in PBL cells and suppressed tumor growth in a chorioallantoic membrane-derived xenograft model of PBL. Overall, our study highlights the pivotal role of the miR-150-5p/E2F3/survivin axis in boosting PBL lymphomagenesis and unveils new therapeutic targets for this lymphoma.
浆母细胞淋巴瘤（PBL）是一种罕见且侵袭性强的B细胞淋巴瘤，预后较差。一些研究描述了PBL中的基因改变，但其转录组研究甚少，驱动淋巴瘤发生的分子机制仍知之甚少。我们的目标是描绘转录组图谱，以识别PBL新型靶向治疗的潜在生物标志物。RNA测序发现PBL中细胞周期相关基因富集，包括MYC和E2F靶点以及参与G2/M检查点的基因。微阵列分析发现了2种取决于MYC易位情况的微小RNA表达特征。有趣的是，miR-150-5p下调，而细胞周期激活剂E2F3和抗凋亡调节因子BIRC5（存活素）上调。在PBL-1细胞中增加miR-150-5p可诱导G1期细胞周期停滞，通过转录抑制E2F3抑制增殖，并通过下调BIRC5促进凋亡。有趣的是，在E2F3敲低的细胞中，miR-150-5p的肿瘤抑制活性减弱。联合抑制E2F3和存活素可减弱PBL细胞中的淋巴瘤发生，并在PBL的绒毛尿囊膜衍生异种移植模型中抑制肿瘤生长。总体而言，我们的研究突出了miR-150-5p/E2F3/存活素轴在促进PBL淋巴瘤发生中的关键作用，并揭示了这种淋巴瘤的新治疗靶点。
