Details

Autor(en) / Beteiligte

• Liang, Huan-Chang
• Costanza, Mariantonia
• Prutsch, Nicole
• Zimmerman, Mark W.
• Gurnhofer, Elisabeth
• Montes-Mojarro, Ivonne A.
• Abraham, Brian J.
• Prokoph, Nina
• Stoiber, Stefan
• Tangermann, Simone
• Lobello, Cosimo
• Oppelt, Jan
• Anagnostopoulos, Ioannis
• Hielscher, Thomas
• Pervez, Shahid
• Klapper, Wolfram
• Zammarchi, Francesca
• Silva, Daniel-Adriano
• Garcia, K. Christopher
• Baker, David
• Janz, Martin
• Schleussner, Nikolai
• Fend, Falko
• Pospíšilová, Šárka
• Janiková, Andrea
• Wallwitz, Jacqueline
• Stoiber, Dagmar
• Simonitsch-Klupp, Ingrid
• Cerroni, Lorenzo
• Pileri, Stefano
• de Leval, Laurence
• Sibon, David
• Fataccioli, Virginie
• Gaulard, Philippe
• Assaf, Chalid
• Knörr, Fabian
• Damm-Welk, Christine
• Woessmann, Wilhelm
• Turner, Suzanne D.
• Look, A. Thomas
• Mathas, Stephan
• Kenner, Lukas
• Merkel, Olaf

Titel

Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma

Ist Teil von

• Nature communications, 2021-09, Vol.12 (1), p.5577-5577, Article 5577

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Abstract Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor ( IL2R )-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.