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The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma

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Item Type:Article
Title:The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma
Creators Name:Schleussner, N., Merkel, O., Costanza, M., Liang, H.C., Hummel, F., Romagnani, C., Durek, P., Anagnostopoulos, I., Hummel, M., Jöhrens, K., Niedobitek, A., Griffin, P.R., Piva, R., Sczakiel, H.L., Woessmann, W., Damm-Welk, C., Hinze, C., Stoiber, D., Gillissen, B., Turner, S.D., Kaergel, E., von Hoff, L., Grau, M., Lenz, G., Dörken, B., Scheidereit, C., Kenner, L., Janz, M. and Mathas, S.
Abstract:Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK(+) and ALK(–) anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK(+) ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17–, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK(+) ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3.
Keywords:Anaplastic Large-Cell Lymphoma, Basic-Leucine Zipper Transcription Factors, Binding Sites, Carrier Proteins, Cell Death, Cell Survival, CRISPR-Cas Systems, Cytokines, Gene Editing, Gene Knockdown Techniques, Neoplastic Gene Expression Regulation, Protein Binding, Protein Kinase Inhibitors, Small Interfering RNA, T-Lymphocyte Subsets, Th17 Cells, Transcription Factor AP-1, Transcriptome, Tumor Cell Line
Publisher:Nature Publishing Group
Page Range:1994-2007
Date:September 2018
Official Publication:https://doi.org/10.1038/s41375-018-0045-9
PubMed:View item in PubMed

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