B Cell Biology Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Department of Immunology, Ophthalmology and ENT, Universidad Complutense de Madrid; Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.
Cell Death Dis. 2023 Oct 18;14(10):687. doi: 10.1038/s41419-023-06178-0.
Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton's tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. The molecular actions of miR-28 and ibrutinib synergistically impair DNA replication by simultaneous inhibition of origin activation and fork progression. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.
弥漫性大 B 细胞淋巴瘤（DLBCL）是最常见的侵袭性 B 细胞淋巴瘤，占 B 细胞非霍奇金淋巴瘤病例的近 40%。DLBCL 通常采用 R-CHOP 化疗进行治疗，但许多患者在治疗后无反应或复发。在这里，我们分析了肿瘤抑制 microRNA-28（miR-28）单独使用和与布鲁顿酪氨酸激酶抑制剂伊布替尼联合使用对 DLBCL 的治疗潜力。miR-28 与伊布替尼联合治疗通过诱导特异性转录细胞周期停滞程序来破坏 DNA 复制，从而增强了两种药物单药治疗的抗肿瘤作用。miR-28 和伊布替尼的分子作用通过同时抑制起始激活和叉进展协同损害 DNA 复制。此外，我们发现 miR-28 加伊布替尼基因特征的下调与 ABC-DLBCL 患者更好的生存相关。这些结果为基于 miRNA 的伊布替尼联合治疗 DLBCL 的有效性提供了证据，并揭示了 miR-28 加伊布替尼基因特征作为 ABC-DLBCL 患者预后的新预测因子。
