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

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

Research output: Journal article (peer-reviewed)Journal article

6 Citations (Scopus)

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.

Original languageEnglish
Article number5577
Pages (from-to)5577
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • Animals
  • Basic-Leucine Zipper Transcription Factors/genetics
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cell Survival/drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoconjugates/pharmacology
  • Interleukin-15/pharmacology
  • Interleukin-2/pharmacology
  • Interleukin-2 Receptor alpha Subunit/genetics
  • Ki-1 Antigen/genetics
  • Lymphoma, Large-Cell, Anaplastic/drug therapy
  • Mice
  • Receptors, Interleukin-2/genetics
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins/genetics
  • Signal Transduction/drug effects
  • Xenograft Model Antitumor Assays

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