The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Rebecca Luchtel, N. Sertac Kip, Xiaoming Xing, Yu Zeng, Zhi Zhang Yang, Jeong Heon Lee, Luciana L. Almada, Sherine F. Elsawa, Ryan A. Knudson, Mark E. Law, Rhett P. Ketterling, Julie M Cunningham, Yanhong Wu, Matthew J. Maurer, Megan M. O'Byrne, James R Cerhan, Susan L Slager, Brian K. Link, Julie C. Porcher, Deanna M. GroteDiane F Jelinek, Ahmet Dogan, Stephen Maxted Ansell, Martin E Fernandez-Zapico, Andrew L Feldman

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3118-3127
Number of pages10
JournalBlood
Volume125
Issue number20
DOIs
StatePublished - May 14 2015

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Peripheral T-Cell Lymphoma
T-cells
Transcription Factors
Feedback
interferon regulatory factor-4
Activation Analysis
Lymphocytes
Cell proliferation
Growth
Non-Hodgkin's Lymphoma
Tumors
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma. / Luchtel, Rebecca; Kip, N. Sertac; Xing, Xiaoming; Zeng, Yu; Yang, Zhi Zhang; Lee, Jeong Heon; Almada, Luciana L.; Elsawa, Sherine F.; Knudson, Ryan A.; Law, Mark E.; Ketterling, Rhett P.; Cunningham, Julie M; Wu, Yanhong; Maurer, Matthew J.; O'Byrne, Megan M.; Cerhan, James R; Slager, Susan L; Link, Brian K.; Porcher, Julie C.; Grote, Deanna M.; Jelinek, Diane F; Dogan, Ahmet; Ansell, Stephen Maxted; Fernandez-Zapico, Martin E; Feldman, Andrew L.

In: Blood, Vol. 125, No. 20, 14.05.2015, p. 3118-3127.

Research output: Contribution to journalArticle

Luchtel, R, Kip, NS, Xing, X, Zeng, Y, Yang, ZZ, Lee, JH, Almada, LL, Elsawa, SF, Knudson, RA, Law, ME, Ketterling, RP, Cunningham, JM, Wu, Y, Maurer, MJ, O'Byrne, MM, Cerhan, JR, Slager, SL, Link, BK, Porcher, JC, Grote, DM, Jelinek, DF, Dogan, A, Ansell, SM, Fernandez-Zapico, ME & Feldman, AL 2015, 'The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma', Blood, vol. 125, no. 20, pp. 3118-3127. https://doi.org/10.1182/blood-2014-05-578575
Luchtel, Rebecca ; Kip, N. Sertac ; Xing, Xiaoming ; Zeng, Yu ; Yang, Zhi Zhang ; Lee, Jeong Heon ; Almada, Luciana L. ; Elsawa, Sherine F. ; Knudson, Ryan A. ; Law, Mark E. ; Ketterling, Rhett P. ; Cunningham, Julie M ; Wu, Yanhong ; Maurer, Matthew J. ; O'Byrne, Megan M. ; Cerhan, James R ; Slager, Susan L ; Link, Brian K. ; Porcher, Julie C. ; Grote, Deanna M. ; Jelinek, Diane F ; Dogan, Ahmet ; Ansell, Stephen Maxted ; Fernandez-Zapico, Martin E ; Feldman, Andrew L. / The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma. In: Blood. 2015 ; Vol. 125, No. 20. pp. 3118-3127.
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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.",
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T1 - The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

AU - Luchtel, Rebecca

AU - Kip, N. Sertac

AU - Xing, Xiaoming

AU - Zeng, Yu

AU - Yang, Zhi Zhang

AU - Lee, Jeong Heon

AU - Almada, Luciana L.

AU - Elsawa, Sherine F.

AU - Knudson, Ryan A.

AU - Law, Mark E.

AU - Ketterling, Rhett P.

AU - Cunningham, Julie M

AU - Wu, Yanhong

AU - Maurer, Matthew J.

AU - O'Byrne, Megan M.

AU - Cerhan, James R

AU - Slager, Susan L

AU - Link, Brian K.

AU - Porcher, Julie C.

AU - Grote, Deanna M.

AU - Jelinek, Diane F

AU - Dogan, Ahmet

AU - Ansell, Stephen Maxted

AU - Fernandez-Zapico, Martin E

AU - Feldman, Andrew L

PY - 2015/5/14

Y1 - 2015/5/14

N2 - 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.

AB - 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.

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