Gut-derived Endotoxin-TLR4 Signaling Drives MYC-Ig Translocation to Promote Lymphoproliferation through c-JUN and STAT3 Activation

Ahmed Rokan, Juan Carlos Hernandez, Rajeshwar Nitiyanandan, Zi Ying Lin, Chia Lin Chen, Tatsuya Machida, Meng Li, Jasleen Khanuja, Mo Li Chen, Stanley M. Tahara, Imran Siddiqi, Keigo Machida

Research output: Contribution to journalArticlepeer-review


Synergism between obesity and virus infection promotes the development of B-cell lymphoma. In this study, we tested whether obesity-associated endotoxin release induced activation-induced cytidine deaminase (AID). TLR4 activation in turn caused c-JUN-dependent 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 lipopolysaccharide stimulation. Accordingly, human patients with lymphoma 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 Toll-like receptor-mediated MYC-Ig translocation via c-JUN-STAT3, leading to lymphoproliferation.

Original languageEnglish
Pages (from-to)155-169
Number of pages15
JournalMolecular Cancer Research
Issue number2
StatePublished - 1 Feb 2023


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