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

Item Type:Article
Title:Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma
Creators Name:Weilemann, A. and Grau, M. and Erdmann, T. and Merkel, O. and Sobhiafshar, U. and Anagnostopoulos, I. and Hummel, M. and Siegert, A. and Hayford, C. and Madle, H. and Wollert-Wulf, B. and Fichtner, I. and Doerken, B. and Dirnhofer, S. and Mathas, S. and Janz, M. and Emre, N.C.T. and Rosenwald, A. and Ott, G. and Lenz, P. and Tzankov, A. and Lenz, G.
Abstract:Anaplastic large cell lymphoma (ALCL) is a distinct entity of T-cell lymphoma that can be divided into two subtypes based on the presence of translocations involving the ALK gene (ALK+ and ALK- ALCL). The transcription factor 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 following IRF4 knockdown demonstrated a significant downregulation of a variety of known MYC target genes. Our analyses furthermore 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 as well as pharmacologic inhibition of MYC signaling was toxic to ALCL cell lines. Collectively, our results demonstrate that ALCLs are dependent on IRF4 and MYC signaling and that MYC might represent a promising target for future therapies.
Keywords:Anaplastic Large-Cell Lymphoma, Cell Survival, Gene Expression Profiling, Inbred NOD Mice, Interferon Regulatory Factors, Lymphoma, Neoplasm Transplantation, Neoplastic Gene Expression Regulation, Proto-Oncogene Proteins c-myc, RNA Interference, Retroviridae, SCID Mice, Signal Transduction, Tumor Cell Line, Animals
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Volume:125
Number:1
Page Range:124-132
Date:1 January 2015
Official Publication:https://doi.org/10.1182/blood-2014-08-594507
PubMed:View item in PubMed

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