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Leukemia. 2018 Sep;32(9):1994-2007. doi: 10.1038/s41375-018-0045-9. Epub 2018 Mar 28.

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

Author information

1
Max-Delbrück-Center for Molecular Medicine, 13125, Berlin, Germany.
2
Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 12200, Berlin, Germany.
3
Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
4
European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge, UK.
5
German Rheumatism Research Centre, German Rheumatism Research Centre (DRFZ), A Leibniz Institute, 10117, Berlin, Germany.
6
Medical Department I, Charité-Universitätsmedizin Berlin, 12200, Berlin, Germany.
7
Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117, Berlin, Germany.
8
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
9
The Scripps Research Institute, Jupiter, FL, 33458, USA.
10
Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, University of Torino, Torino, Italy.
11
NHL-BFM Study Centre and Department of Paediatric Haematology and Oncology, Justus-Liebig-University, Giessen, Germany.
12
Department of Nephrology, Charité-Universitätsmedizin Berlin, 12200, Berlin, Germany.
13
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria.
14
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
15
Department of Pathology, University of Cambridge, Cambridge, CB21QP, UK.
16
Department of Medicine A, Albert-Schweitzer-Campus 1, University Hospital Münster, 48149, Münster, Germany.
17
Cluster of Excellence EXC 1003, Cells in Motion, 48149, Münster, Germany.
18
Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria. lukas.kenner@meduniwien.ac.at.
19
European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge, UK. lukas.kenner@meduniwien.ac.at.
20
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria. lukas.kenner@meduniwien.ac.at.
21
University of Veterinary Medicine, Vienna, Austria. lukas.kenner@meduniwien.ac.at.
22
CBmed, Center for Biomarker Research in Medicine, 8010, Graz, Austria. lukas.kenner@meduniwien.ac.at.
23
Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, 13125, Berlin, Germany.
24
Max-Delbrück-Center for Molecular Medicine, 13125, Berlin, Germany. stephan.mathas@charite.de.
25
Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, 12200, Berlin, Germany. stephan.mathas@charite.de.
26
European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge, UK. stephan.mathas@charite.de.
27
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. stephan.mathas@charite.de.
28
Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, 13125, Berlin, Germany. stephan.mathas@charite.de.

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/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.

PMID:
29588546
PMCID:
PMC6127090
DOI:
10.1038/s41375-018-0045-9
[Indexed for MEDLINE]
Free PMC Article

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