title: c-Myc dysregulation is a co-transforming event for nuclear factor-κB activated B cells.
abstract: 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 vivoactivation 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.
authors.affiliation: CNRS-UMR 7276, University of Limoges, France.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: David
authors.affiliation: CNRS-UMR 7276, University of Limoges, France.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Arnaud
authors.affiliation: CNRS-UMR 7276, University of Limoges, France.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Fradet
authors.affiliation: CNRS-UMR 7276, University of Limoges, France.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Lascaux
authors.affiliation: CNRS-UMR 7276, University of Limoges, France.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.|Platform of Cytometry and Imagery (CIM), University of Limoges, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ouk-Martin
authors.affiliation: CNRS-UMR 7276, University of Limoges, France.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gachard
authors.affiliation: Research Unit Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
authors.affiliation: CNRS-UMR 7276, University of Limoges, France.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Feuillard
authors.affiliation: CNRS-UMR 7276, University of Limoges, France nathalie.faumont@unilim.fr.|Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Faumont
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000235:genetics; D002472:Cell Transformation, Viral; D020869:Gene Expression Profiling / Q000379:methods; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019013:CD40 Antigens; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc