c-Myc dysregulation is a co-transforming event for nuclear factor-κB activated B cells
| Title: | c-Myc dysregulation is a co-transforming event for nuclear factor-κB activated B cells |
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| Authors: | Amandine David, Nicolas Arnaud, Magali Fradet, Hélène Lascaux, Catherine Ouk-Martin, Nathalie Gachard, Ursula Zimber-Strobl, Jean Feuillard, Nathalie Faumont |
| Source: | Haematologica, Vol 102, Iss 5 (2017) |
| Publisher Information: | Ferrata Storti Foundation, 2017. |
| Publication Year: | 2017 |
| Collection: | LCC:Diseases of the blood and blood-forming organs |
| Subject Terms: | Diseases of the blood and blood-forming organs, RC633-647.5 |
| More Details: | While c-Myc dysregulation is constantly associated with highly proliferating B-cell tumors, nuclear factor (NF)-κB addiction is found in indolent lymphomas as well as diffuse large B-cell lymphomas, either with an activated B-cell like phenotype or associated with the Epstein-Barr virus. We raised the question of the effect of c-Myc in B cells with NF-κB activated by three different inducers: Epstein-Barr virus-latency III program, TLR9 and CD40. Induction of c-Myc overexpression increased proliferation of Epstein-Barr virus-latency III immortalized B cells, an effect that was dependent on NF-κB. Results from transcriptomic signatures and functional studies showed that c-Myc overexpression increased Epstein-Barr virus-latency III-driven proliferation depending on NF-κB. In vitro, induction of c-Myc increased proliferation of B cells with TLR9-dependant activation of MyD88, with decreased apoptosis. In the transgenic λc-Myc mouse model with c-Myc overexpression in B cells, in vivo activation of MyD88 by TLR9 induced splenomegaly related to an increased synthesis phase (S-phase) entry of B cells. Transgenic mice with both continuous CD40 signaling in B cells and the λc-Myc transgene developed very aggressive lymphomas with characteristics of activated diffuse large B-cell lymphomas. The main characteristic gene expression profile signatures of these tumors were those of proliferation and energetic metabolism. These results suggest that c-Myc is an NF-κB co-transforming event in aggressive lymphomas with an activated phenotype, activated B-cell like diffuse large B-cell lymphomas. This would explain why NF-κB is associated with both indolent and aggressive lymphomas, and opens new perspectives on the possibility of combinatory therapies targeting both the c-Myc proliferating program and NF-κB activation pathways in diffuse large B-cell lymphomas. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 0390-6078 1592-8721 |
| Relation: | https://haematologica.org/article/view/8068; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721 |
| DOI: | 10.3324/haematol.2016.156281 |
| Access URL: | https://doaj.org/article/2bdea7433ec941de88401744e3e458f5 |
| Accession Number: | edsdoj.2bdea7433ec941de88401744e3e458f5 |
| Database: | Directory of Open Access Journals |
| ISSN: | 03906078 15928721 |
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| DOI: | 10.3324/haematol.2016.156281 |
| Published in: | Haematologica |
| Language: | English |