The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.
Griffin, Patrick R
Sczakiel, Henrike L
von Hoff, Linda
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Schleussner, N., Merkel, O., Costanza, M., Liang, H., Hummel, F., Romagnani, C., Durek, P., et al. (2018). The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.. Leukemia, 32 (9), 1994-2007. https://doi.org/10.1038/s41375-018-0045-9
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 / innate lymphoid cell type 3 (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORt. 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 to 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 a subset of ALCL might originate from ILC3.
T-Lymphocyte Subsets, Cell Line, Tumor, Humans, Carrier Proteins, Transcription Factor AP-1, RNA, Small Interfering, Cytokines, Protein Kinase Inhibitors, Cell Death, Cell Survival, Gene Expression Regulation, Neoplastic, Binding Sites, Protein Binding, Basic-Leucine Zipper Transcription Factors, Lymphoma, Large-Cell, Anaplastic, Gene Knockdown Techniques, Th17 Cells, Transcriptome, CRISPR-Cas Systems, Gene Editing
Leukaemia & Lymphoma Research (12065)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675712)
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External DOI: https://doi.org/10.1038/s41375-018-0045-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/274128
Attribution-NonCommercial-ShareAlike 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-sa/4.0/