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 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.

EBV Latency III–Transformed B Cells Are Inducers of Conventional and Unconventional Regulatory T Cells in a PD-L1–Dependent Manner

“…Transcriptome results suggested that PD-L1 expression during EBV latency III/proliferation program was mainly due to LMP1, the main EBV oncogene (unpublished data and ( [20]). To confirm this result, the EREB2-5 cell line, an EBV latency III cell line that is estradiol conditional for EBNA2 activity (essential for the initiation of the latency III program expression) (21) was stably transfected with the doxycycline-regulatable PRT1 vector in which the cassette was a cDNA coding for either Luc, LMP1-Wt, or a dominant negative variant of LMP1, LMP1-CT (22).…”

Pre-Clinical Blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma

“…Our previous transcriptome studies from L.CD40 mice suggested that those tumors might express high levels of CD274/PD-L1 (6). We thus analyzed the Immune Escape Gene Signature published by C Laurent et al (Supplemental Table 1) (7) from the Affymetrix transcriptome (HT MG-430 PM Array, Supplemental Tables 2 and 3) of a series of six L.CD40 B-cell lymphomas that were compared to their CD19_Cre littermate.…”

Morpho‐Functional Characteristics of Bone Marrow Multipotent Mesenchymal Stromal Cells after Activation or Inhibition of Epidermal Growth Factor and Toll‐Like Receptors or Treatment with DNA Intercalator Cisplatin

“…In the case of TA application, p38 MAPK can also be involved. In addition, the TA can activate the classical signal cascade of TLR, activation ends by the expression induction of many genes, including с-Myc, via NF-kB transcriptional factor (50). Furthermore, MAPK induces the transcription of early c-Fos and c-Myc genes, which produce transcription factors and provide the transcription of late genes responsible for proliferation, survival, and cell motility (23).…”

“…Furthermore, MAPK induces the transcription of early c-Fos and c-Myc genes, which produce transcription factors and provide the transcription of late genes responsible for proliferation, survival, and cell motility (23). In addition, the TA can activate the classical signal cascade of TLR, activation ends by the expression induction of many genes, including с-Myc, via NF-kB transcriptional factor (50). As a matter of fact, a high expression of c-Myc is usually observed during active cell growth and proliferation (51).…”