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

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...

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Bibliographic Details
Published in:Cell death & disease 2023-10, Vol.14 (10), p.687-687, Article 687
Main Authors: Fuertes, Teresa, Álvarez-Corrales, Emigdio, Gómez-Escolar, Carmen, Ubieto-Capella, Patricia, Serrano-Navarro, Álvaro, de Molina, Antonio, Méndez, Juan, Ramiro, Almudena R., de Yébenes, Virginia G.
Format: Article
Language:English
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Antibodies
B-cell lymphoma
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Chemotherapy
Combination therapy
Deoxyribonucleic acid
DNA
DNA biosynthesis
Immunology
Kinases
Life Sciences
Lymphoma
MicroRNAs
miRNA
Non-Hodgkin's lymphoma
Protein-tyrosine kinase
Replication
Tumor suppressor genes
Tumors
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06178-0