2. Academic Validation
  3. miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication

miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication

  • Cell Death Dis. 2023 Oct 18;14(10):687. doi: 10.1038/s41419-023-06178-0.
Teresa Fuertes 1,  Emigdio Álvarez-Corrales 2,  Carmen Gómez-Escolar 1,  Patricia Ubieto-Capella 3,  Álvaro Serrano-Navarro 1,  Antonio de Molina 4,  Juan Méndez 3,  Almudena R Ramiro # 5,  Virginia G de Yébenes # 6
Affiliations

Affiliations

  • 1 B Cell Biology Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 2 Department of Immunology, Ophthalmology and ENT, Universidad Complutense de Madrid; Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.
  • 3 DNA replication Group. Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
  • 4 Comparative Medicine Unit. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 5 B Cell Biology Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. aramiro@cnic.es.
  • 6 Department of Immunology, Ophthalmology and ENT, Universidad Complutense de Madrid; Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain. vgarciay@ucm.es.
  • # Contributed equally.
PMID: 37852959 DOI: 10.1038/s41419-023-06178-0
Abstract

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.

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