CD40 plays a vital role in humoral immunity, via its potent and multifaceted function as an activating receptor of various immune cells, most notably B lymphocytes. The Epstein-Barr virus-encoded transforming protein latent membrane protein 1 (LMP1) serves as a functional mimic of CD40 signals to B cells but lacks key regulatory controls that restrain CD40 signaling. This allows LMP1 to activate B cells in an abnormal manner that can contribute to the pathogenesis of human B-cell lymphoma and autoimmune disease. This review focuses upon a comparative analysis of CD40 versus LMP1 functions and mechanisms of action in B lymphocytes, discussing how this comparison can provide valuable information on both how CD40 signaling is normally regulated and how LMP1 disrupts the normal CD40 pathways, which can provide information of value to therapeutic design.

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Gene regulation is fine-tuned by a dynamic balance between transcriptionally activating and repressive modifications of histone tails. It has been well-established that lysine and arginine methylation can be reversed by two groups of evolutionarily conserved enzymes known as histone demethylases, which have been shown to play critical roles in development, differentiation and diseases like cancer. Recent work has demonstrated demethylase-independent functions of these proteins, highlighting the complex mechanisms by which these proteins exert their effects on gene expression. Here we discuss the roles of lysine 27 demethylases, JMJD3 and UTX, in cancer and potential therapeutic avenues targeting these enzymes. Despite a high degree of sequence similarity in the catalytic domain between JMJD3 and UTX, numerous studies revealed surprisingly contrasting roles in cellular reprogramming and cancer, particularly leukemia. Understanding the demethylase-dependent and – independent functions of the enzymes affecting histone methylation, their posttranslational modifications and participation in different complexes as well as in vivo modeling of the mutations affecting those enzymes in cancer can shed light on their unique physiological roles. This information cumulated in the future will aid in the development of improved inhibitors to treat cancers affected by demethylase mutations and aberrant gene activation.

These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.

The Epstein-Barr virus (EBV)-encoded protein latent membrane protein 1 (LMP1) is essential for EBV-mediated B cell transformation and plays a critical role in the development of post-transplant B cell lymphomas. LMP1 also contributes to the exacerbation of autoimmune diseases such as systemic lupus erythematosus (SLE). LMP1 is a functional mimic of the tumor necrosis factor receptor (TNFR) superfamily member CD40, and relies on TNFR-associated factor (TRAF) adaptor proteins to mediate signaling. However, LMP1 activation signals to the B cell are amplified and sustained compared to CD40 signals. We previously demonstrated that LMP1 and CD40 use TRAF molecules differently. Although associating with CD40 and LMP1 via separate mechanisms, TRAF6 plays a significant role in signal transduction by both. It is unknown whether TRAF6 mediates CD40 versus LMP1 functions via distinct or shared pathways. In this study, we tested the hypothesis that TRAF6 uses the kinase TAK1 to trigger important signaling pathways following both CD40 and LMP1 stimulation. We determined that TAK1 was required for JNK activation and interleukin-6 (IL-6) production mediated by CD40 and LMP1, in both mouse and human B cells. Additionally, TRAF3 negatively regulated TRAF6-dependent, CD40-mediated TAK1 activation by limiting TRAF6 recruitment. This mode of regulation was not observed for LMP1 and may contribute to the dysregulation of LMP1 compared to CD40 signals.