期刊
HAEMATOLOGICA
卷 102, 期 5, 页码 883-894出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2016.156281
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类别
资金
- Ligue National contre le Cancer (Equipe Labellisee Ligue)
- Institut National contre le Cancer (INCa)
- Comite Orientation Recherche Cancer (CORC)
- Limousin Region
- Haute Vienne comitee of the Ligue Nationale contre le Cancer
- Correze comitee of the Ligue Nationale contre le Cancer
- Lyons Club of Correze
- DFG [GZ: ZI 1382/4-1]
While c-Myc dysregulation is constantly associated with highly proliferating B-cell tumors, nuclear factor (NF)-kappa B 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-kappa B 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-kappa B. Results from transcriptomic signatures and functional studies showed that c-Myc overexpression increased Epstein-Barr virus-latency III-driven proliferation depending on NF-kappa B. In vitro, induction of c-Myc increased proliferation of B cells with TLR9-dependant activation of MyD88, with decreased apoptosis. In the transgenic lc-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 lc-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-kappa B co-transforming event in aggressive lymphomas with an activated phenotype, activated B-cell like diffuse large B-cell lymphomas. This would explain why NF-kappa B 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-kappa B activation pathways in diffuse large B-cell lymphomas.
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