The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma
| Autor: | Mariantonia Costanza, Wilhelm Woessmann, Claus Scheidereit, Suzanne D. Turner, Michael Hummel, Stephan Mathas, Linda von Hoff, Georg Lenz, Michael Grau, Antonia Niedobitek, Christian Hinze, Henrike L Sczakiel, Chiara Romagnani, Christine Damm-Welk, Franziska Hummel, Bernd Dörken, Korinna Jöhrens, Olaf Merkel, Huan-Chang Liang, Patrick R. Griffin, Martin Janz, Bernd Gillissen, Roberto Piva, Ioannis Anagnostopoulos, Dagmar Stoiber, Eva Kaergel, Pawel Durek, Lukas Kenner, Nikolai Schleussner |
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| Přispěvatelé: | Costanza, Mariantonia [0000-0002-8959-1083], Apollo - University of Cambridge Repository |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Cancer Research medicine.drug_class Cell Survival Article 03 medical and health sciences T-Lymphocyte Subsets Hematology Oncology hemic and lymphatic diseases Cell Line Tumor BATF medicine Humans RNA Small Interfering Anaplastic large-cell lymphoma Protein Kinase Inhibitors Gene Editing Binding Sites Crizotinib Cell Death Chemistry Large cell medicine.disease Lymphoma ALK inhibitor Gene Expression Regulation Neoplastic Transcription Factor AP-1 030104 developmental biology Basic-Leucine Zipper Transcription Factors Gene Knockdown Techniques Cancer research Cytokines Lymphoma Large-Cell Anaplastic Th17 Cells CRISPR-Cas Systems Carrier Proteins Transcriptome IRF4 medicine.drug Protein Binding |
| Zdroj: | Leukemia BASE-Bielefeld Academic Search Engine |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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