Journal
BLOOD
Volume 125, Issue 20, Pages 3118-3127Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-05-578575
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Funding
- American Cancer Society [RSG-12-193-01-TBE]
- Karl-Erivan Haub Family Career Development Award in Cancer Research at the Mayo Clinic in Rochester
- National Institutes of Health National Cancer Institute [R01 CA177734, R01 CA92153, R01 CA1144, P30 CA15083, P50CA97274]
- National Center for Advancing Translational Science (CTSA) [UL1 TR000135]
- China Scholarship Council
- Damon Runyon Cancer Research Foundation [CI-48-09]
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Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor kappa B (NF-kappa B) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kappa B subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-kappa B, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kappa B inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.
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