Journal article
The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma
Blood, Vol.125(20), pp.3118-3127
05/14/2015
DOI: 10.1182/blood-2014-05-578575
PMCID: PMC4432006
PMID: 25833963
Abstract
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 κB (NF-κB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB 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-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.
Details
- Title: Subtitle
- The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma
- Creators
- Rebecca L Boddicker - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNJames R Cerhan - Department of Health Sciences Research, Mayo Clinic, Rochester, MNN Sertac Kip - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNBrian K Link - Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA; andAhmet Dogan - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNXiaoming Xing - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Department of Pathology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, ChinaYu Zeng - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, ChinaZhi-Zhang Yang - Division of HematologyJeong-Heon Lee - Epigenomics Translational Program, Center for Individualized MedicineLuciana L Almada - Schulze Center for Novel Therapeutics, Division of Oncology Research, andSherine F Elsawa - Schulze Center for Novel Therapeutics, Division of Oncology Research, andRyan A Knudson - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNMark E Law - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNRhett P Ketterling - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNJulie M Cunningham - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNYanhong Wu - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNMatthew J Maurer - Department of Health Sciences Research, Mayo Clinic, Rochester, MNMegan M O'Byrne - Department of Health Sciences Research, Mayo Clinic, Rochester, MNSusan L Slager - Department of Health Sciences Research, Mayo Clinic, Rochester, MNJulie C Porcher - Division of HematologyDeanna M Grote - Division of HematologyDiane F Jelinek - Division of Hematology, Department of Immunology, Mayo Clinic, Rochester, MNStephen M Ansell - Division of HematologyMartin E Fernandez-Zapico - Schulze Center for Novel Therapeutics, Division of Oncology Research, andAndrew L Feldman - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.125(20), pp.3118-3127
- DOI
- 10.1182/blood-2014-05-578575
- PMID
- 25833963
- PMCID
- PMC4432006
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- R01 CA092153 / NCI NIH HHS R01 CA1144 / NCI NIH HHS UL1 TR000135 / NCATS NIH HHS R01 CA92153 / NCI NIH HHS P30 CA15083 / NCI NIH HHS R01 CA177734 / NCI NIH HHS P50CA97274 / NCI NIH HHS P30 CA015083 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
- Language
- English
- Date published
- 05/14/2015
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
- Record Identifier
- 9984094522402771
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