Zeitschriftenaufsatz
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2018
The AP-1-BATF and-BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma
Autor:in
Schleussner, Nikolai; Merkel, Olaf; Costanza, Mariantonia; Liang, Huan-Chang; Hummel, Franziska; Romagnani, Chiara; Durek, Pawel; Anagnostopoulos, Ioannis; Humme, M; Joehrens, Korinna; Niedobitek, Antonia; Griffin, Patrick R.; Piva, Roberto; Sczakiel, Henrike Lisa; Woessmann, Wilhelm; Damm-Welk, Christine; Hinze, Christian; Stoiber, Dagmar; Gillissen, Bernhard; Turner, Suzanne; Kaergel, Eva; von Hoff, Linda; Grau, Michael; Lenz, Georg; Dorken, Bernd; Scheidereit, Claus; Kenner, Lukas; Janz, Martin; Mathas, Stephan
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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 BA IF and BA IF3 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 ROR gamma t. 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.
Schlagwörter
Basic-Leucine Zipper Transcription Factorsmetabolism; Binding Sites; CRISPR-Cas Systems; Carrier Proteinsmetabolism; Cell Deathgenetics; Cell Line, Tumor; Cell Survival; Cytokinesmetabolism; Gene Editing; Gene Expression Regulation, Neoplasticdrug effects; Gene Knockdown Techniques; Humans; Lymphoma, Large-Cell, Anaplasticetiologymetabolismpathology; Protein Binding; Protein Kinase Inhibitorspharmacology; RNA, Small Interferinggenetics; T-Lymphocyte Subsetsimmunologymetabolism; Th17 Cellsimmunologymetabolism; Transcription Factor AP-1metabolism; Transcriptome
Dokumententyp
Originalarbeit
CC Lizenz
CCBYNCSA
Open Access Type
Hybrid
ISSN/eISSN
0887-6924 - 1476-5551
10.1038/s41375-018-0045-9
WoS ID
PubMed ID