miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication
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 th...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06178-0 |
| _version_ | 1797653564687908864 |
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| author | Teresa Fuertes Emigdio Álvarez-Corrales Carmen Gómez-Escolar Patricia Ubieto-Capella Álvaro Serrano-Navarro Antonio de Molina Juan Méndez Almudena R. Ramiro Virginia G. de Yébenes |
| author_facet | Teresa Fuertes Emigdio Álvarez-Corrales Carmen Gómez-Escolar Patricia Ubieto-Capella Álvaro Serrano-Navarro Antonio de Molina Juan Méndez Almudena R. Ramiro Virginia G. de Yébenes |
| author_sort | Teresa Fuertes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T16:46:26Z |
| format | Article |
| id | doaj.art-9379e2de340e481cb06088a6a79cb0c0 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T16:46:26Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9379e2de340e481cb06088a6a79cb0c02023-10-22T11:29:11ZengNature Publishing GroupCell Death and Disease2041-48892023-10-01141011310.1038/s41419-023-06178-0miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replicationTeresa Fuertes0Emigdio Álvarez-Corrales1Carmen Gómez-Escolar2Patricia Ubieto-Capella3Álvaro Serrano-Navarro4Antonio de Molina5Juan Méndez6Almudena R. Ramiro7Virginia G. de Yébenes8B Cell Biology Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC)Department of Immunology, Ophthalmology and ENT, Universidad Complutense de Madrid; Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12)B Cell Biology Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC)DNA replication Group. Centro Nacional de Investigaciones Oncológicas (CNIO)B Cell Biology Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC)Comparative Medicine Unit. Centro Nacional de Investigaciones Cardiovasculares (CNIC)DNA replication Group. Centro Nacional de Investigaciones Oncológicas (CNIO)B Cell Biology Laboratory Centro Nacional de Investigaciones Cardiovasculares (CNIC)Department of Immunology, Ophthalmology and ENT, Universidad Complutense de Madrid; Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12)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.https://doi.org/10.1038/s41419-023-06178-0 |
| spellingShingle | Teresa Fuertes Emigdio Álvarez-Corrales Carmen Gómez-Escolar Patricia Ubieto-Capella Álvaro Serrano-Navarro Antonio de Molina Juan Méndez Almudena R. Ramiro Virginia G. de Yébenes miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication Cell Death and Disease |
| title | miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication |
| title_full | miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication |
| title_fullStr | miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication |
| title_full_unstemmed | miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication |
| title_short | miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication |
| title_sort | mir 28 based combination therapy impairs aggressive b cell lymphoma growth by rewiring dna replication |
| url | https://doi.org/10.1038/s41419-023-06178-0 |
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