Gut-derived endotoxin-TLR4 signaling drives MYC-Ig translocation to promote lymphoproliferation through c-JUN and STAT3 activation.

Synergism between obesity and virus infection promotes the development of B-cell lymphoma. In this study, we tested if obesity associated endotoxin release induced activation-induced cytidine deaminase (AID). TLR4 activation in turn caused c-JUN and STAT3 dependent translocations of MYC loci to suppress transactivation of CD95/FAS. We used viral nucleocapside Core transgenic (Tg) mice fed alcohol Western diet to determine whether oncogenesis arising from obesity and chronic virus infection occurred through TLR4-c-JUN-STAT3 pathways. Our results showed B-cell-specific, c-Jun and/or Stat3 disruption reduced the incidence of splenomegaly in these mice. AID-dependent t(8;14) translocation was observed between the Ig promoter and MYC loci. Comparison with human B cells showed MYC-immunoglobulin (Ig) translocations after virus infection with LPS stimulation. Accordingly, human lymphoma patients with virus infections and obesity showed a 40% incidence of MYC-Ig translocations. Thus, obesity and virus infection promote AID-mediated translocation between the Ig promoter and MYC through the TLR4-c-JUN axis, resulting in lymphoproliferation. Taken together, preventative treatment targeting either c-JUN and/or STAT3 may be effective strategies to prevent tumor development. Implications: Obesity increases gut-derived endotoxin which induces TLR-mediated MYC-Ig translocation via c-JUN-STAT3, leading to lymphoproliferation.