%0 Journal Article
%A Fuertes, Teresa
%A Álvarez Corrales, Emigdio
%A Gómez Escolar, Carmen
%A Ubieto Capella, Patricia
%A Serrano Navarro, Álvaro
%A De Molina, Antonio
%A Méndez, Juan
%A Ramiro, Almudena 
%A García-Yébenes Mena, Virginia Pilar
%A García-Yébes Mena, Virginia Pilar
%T miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication
%D 2023
%@ 2041-4889
%U https://hdl.handle.net/20.500.14352/88881
%X 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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