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Type of publication: Journal Article
Type of document: Full Paper

Year: 2018

Authors: Schleussner, N; Merkel, O; Costanza, M; Liang, HC; Hummel, F; Romagnani, C; Durek, P; Anagnostopoulos, I; Hummel, M; Jöhrens, K; Niedobitek, A; Griffin, PR; Piva, R; Sczakiel, HL; Woessmann, W; Damm-Welk, C; Hinze, C; Stoiber, D; Gillissen, B; Turner, SD; Kaergel, E; von Hoff, L; Grau, M; Lenz, G; Dörken, B; Scheidereit, C; Kenner, L; Janz, M; Mathas, S

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

Source: Leukemia. 2018; 32(9):1994-2007



Authors Vetmeduni Vienna:

Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals


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.

Keywords Pubmed: 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

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