Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma

Weilemann, André; Grau, Michael; Erdmann, Tabea; Merkel, Olaf; Sobhiafshar, Ulduz; Anagnostopoulos, Ioannis; Hummel, Michael; Siegert, Antje; Hayford, Claudia; Madle, Hannelore; Wollert-Wulf, Brigitte; Fichtner, Iduna; Dörken, Bernd; Dirnhofer, Stephan; Mathas, Stephan; Janz, Martin; Emre, N. C. Tolga; Rosenwald, Andreas; Ott, German; Lenz, Peter; Tzankov, Alexandar; Lenz, Georg

doi:10.1182/blood-2014-08-594507

Cited by 105 publications

(123 citation statements)

References 43 publications

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“…In multiple myeloma, 10 and as recently demonstrated in PTCL, 36 IRF4 transcriptionally regulates MYC and drives tumor cell proliferation. The site at which IRF4 binds to the MYC promoter in PTCL (1486 bp upstream MYC) corresponds to the IRF4 binding site previously reported in myeloma.…”

Section: Discussionmentioning

confidence: 99%

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

Boddicker

Kip

Xing

et al. 2015

Blood

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• The NF-kB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells.• A positive feedback loop involving CD30, NF-kB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-kB inhibitors.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 kB (NF-kB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kB 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-kB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. (Blood. 2015; 125(20):3118-3127) Introduction Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas (NHLs) characterized by poor overall survival rates. [1][2][3] Most patients are treated with anthracycline-based chemotherapy regimens originally designed for B-cell lymphomas. Five-year overall survival rates vary somewhat by subtype but average ;35%. The possibility of individualized targeted therapy holds promise, but advances have been hindered by the fact that few therapeutic targets have been identified and validated in PTCLs. Our group's approach to this challenge has been to characterize the genetics of PTCLs to identify novel biomarkers and therapeutic targets. We have focused particularly on chromosomal translocations, which have played a major role in identifying diagnostic, prognostic, and theranostic biomarkers in hematologic neoplasms in general (eg, BCR-ABL) and PTCLs specifically (ALK rearrangements). 4,5 We previously discovered a recurrent translocation in PTCL, t(6;14)(p25.3;q11.2), that juxtaposes the interferon regulatory factor-4 (IRF4) and T-cell receptor-a (TRA) genes and is associated with increased IRF4 expression. 6 Because TRA translocation partners typically function as oncogenes in T-cell malignancies, we postulated that IRF4 plays an oncogenic role in PTCLs.7 IRF4 is a tightly regulated transcription factor involved in growth and differentiation of normal T and B lymp...

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Section: Discussionmentioning

confidence: 99%

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

Boddicker

Kip

Xing

et al. 2015

Blood

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“…Because these practices are relatively new, their impact on risk for SN is poorly understood. Most studies have shown no association, 22,36,38,41 but they are generally small with limited follow-up.…”

Section: Disease- and Transplant-related Risk Factorsmentioning

confidence: 99%

“…39,125 However, the role of TBI in SN risk remains unresolved, with six publications providing strong evidence of increased SN risk from TBI exposure, 16,17,32,46,49,60 and eight studies failing to identify an association between TBI and SN. 22,24,33,37,38,41,59,69 …”

Section: Disease- and Transplant-related Risk Factorsmentioning

confidence: 99%

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

Morton

Saber

Baker

et al. 2017

Biology of Blood and Marrow Transplantation

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Subsequent neoplasms (SN) following hematopoietic cell transplantation (HCT) cause significant patient morbidity and mortality. Risks for specific SN types vary substantially, with particularly elevated risks for post-transplant lymphoproliferative disorders, myelodysplastic syndrome/acute myeloid leukemia, and squamous cell malignancies. This consensus document provides an overview of the current state of knowledge regarding SN after HCT and recommends priorities and approaches to overcome challenges and gaps in understanding. Numerous factors have been suggested to impact risk, including patient-related (e.g., age), primary disease-related (e.g., disease type, pre-HCT therapies), and HCT-related characteristics (e.g., type and intensity of conditioning regimen, stem cell source, development of graft-versus-host disease). However, gaps in understanding remain for each of these risk factors, particularly for patients receiving HCT in the current era due to substantial advances in clinical transplantation practices. Additionally, the influence of non-transplant-related risk factors (e.g., germline genetic susceptibility, oncogenic viruses, lifestyle factors) is poorly understood. Clarification of the magnitude of SN risks and identification of etiologic factors will require large-scale, long-term, systematic follow-up of HCT survivors with detailed clinical data. Most investigations of the mechanisms of SN pathogenesis after HCT have focused on immune drivers. Expansion of our understanding in this area will require interdisciplinary laboratory collaborations utilizing measures of immune function and availability of archival tissue from SN diagnoses. Consensus-based recommendations for optimal preventative, screening, and therapeutic approaches have been developed for certain SN after HCT, whereas for other SN, general population guidelines are recommended. Further evidence is needed to specifically tailor preventative, screening, and therapeutic guidelines for SN after HCT, particularly for unique patient populations. Accomplishment of this broad research agenda will require increased investment in systematic data collection with engagement from patients, clinicians, and interdisciplinary scientists in order to reduce the burden of SN in the rapidly growing population of HCT survivors.

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“…Weilemann et al [15] investigated ALCL as well as focusing on the interferon regulatory factor 4 (IRF4), known to be highly expressed in both ALK-positive and ALK-negative cases. They show that ALCLs of both subtypes are addicted to IRF4 signaling, as knockdown of IRF4 by RNA interference was toxic to ALCL cell lines in vitro and in ALCL xenograft mouse models in vivo.…”

Section: Biology Of Lymphomamentioning

confidence: 99%

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2014–December 2014

Krieken

2015

J Hematopathol

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Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma

Cited by 105 publications

References 43 publications

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

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

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2014–December 2014

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