title: The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma.
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.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Boddicker
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: N Sertac
authors.initials: NS
authors.lastname: Kip
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Department of Pathology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, China;
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xing
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Division of Hematology.
authors.forename: Zhi-Zhang
authors.initials: ZZ
authors.lastname: Yang
authors.affiliation: Epigenomics Translational Program, Center for Individualized Medicine.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, and.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, and.
authors.forename: Sherine F
authors.initials: SF
authors.lastname: Elsawa
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Knudson
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Mark E
authors.initials: ME
authors.lastname: Law
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN;
authors.forename: Megan M
authors.initials: MM
authors.lastname: O'Byrne
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN;
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN;
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.affiliation: Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA; and.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Link
authors.affiliation: Division of Hematology.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Porcher
authors.affiliation: Division of Hematology.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Grote
authors.affiliation: Division of Hematology, Department of Immunology, Mayo Clinic, Rochester, MN.
authors.forename: Diane F
authors.initials: DF
authors.lastname: Jelinek
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogan
authors.affiliation: Division of Hematology.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, and.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056915:DNA Copy Number Variations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D017730:Ki-1 Antigen / Q000378:metabolism*; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D011110:Polymorphism, Genetic; D014158:Transcription, Genetic; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D017730:Ki-1 Antigen; D016328:NF-kappa B; D000099218:Interferon Regulatory Factor-4
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