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Blood. 2015 Jan 1;125(1):124-32. doi: 10.1182/blood-2014-08-594507. Epub 2014 Oct 30.

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

Author information

1
Department of Medicine A, Translational Oncology, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany; Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Cells in Motion Cluster of Excellence, Münster, Germany; Mathematisch-Naturwissenschaftliche Fakultät I, Humboldt University Berlin, Berlin, Germany;
2
Department of Physics, Philipps-University, Marburg, Germany;
3
Department of Medicine A, Translational Oncology, Albert-Schweitzer Campus 1, University Hospital Münster, Münster, Germany; Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Cells in Motion Cluster of Excellence, Münster, Germany;
4
Department of Experimental Pathology, Medical University Vienna, Wien, Austria;
5
Department of Molecular Biology and Genetics, Boğaziçi University, Bebek, Istanbul, Turkey;
6
Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany;
7
Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany;
8
Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany;
9
Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany;
10
Institute of Pathology, University Hospital, Basel, Switzerland;
11
Department of Pathology, University of Würzburg, Würzburg, Germany; and.
12
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany.

Abstract

Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into 2 subtypes based on the presence of translocations involving the ALK gene (ALK(+) and ALK(-) ALCL). The interferon regulatory factor 4 (IRF4) is known to be highly expressed in both ALK(+) and ALK(-) ALCLs. However, the role of IRF4 in the pathogenesis of these lymphomas remains unclear. Here we 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. Gene expression profiling after IRF4 knockdown demonstrated a significant downregulation of a variety of known MYC target genes. Furthermore, our analyses revealed that MYC is a primary target of IRF4, identifying a novel regulatory mechanism of MYC expression and its target gene network in ALCL. MYC, itself, is essential for ALCL survival, as both knockdown of MYC and pharmacologic inhibition of MYC signaling were toxic to ALCL cell lines. Collectively, our results demonstrate that ALCLs are dependent on IRF4 and MYC signaling and that MYC may represent a promising target for future therapies.

PMID:
25359993
DOI:
10.1182/blood-2014-08-594507
[Indexed for MEDLINE]
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