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 Baker, Martin Janz, Nikolai Schleussner, Falko Fend, Šárka Pospíšilová, Andrea Janiková, Jacqueline Wallwitz, Dagmar Stoiber, Ingrid Simonitsch-Klupp, Lorenzo Cerroni, Stefano Pileri, Laurence 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 () and Olaf Merkel ()
Additional contact information
Huan-Chang Liang: Medical University of Vienna
Mariantonia Costanza: Suzanne Turner
Nicole Prutsch: Harvard Medical School
Mark W. Zimmerman: Harvard Medical School
Elisabeth Gurnhofer: Medical University of Vienna
Ivonne A. Montes-Mojarro: Suzanne Turner
Brian J. Abraham: St. Jude Children’s Research Hospital
Nina Prokoph: Suzanne Turner
Stefan Stoiber: Medical University of Vienna
Simone Tangermann: University of Veterinary Medicine Vienna
Cosimo Lobello: Suzanne Turner
Jan Oppelt: Masaryk University
Ioannis Anagnostopoulos: University of Würzburg
Thomas Hielscher: German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ)
Shahid Pervez: Aga Khan University Hospital
Wolfram Klapper: University Hospital Schleswig-Holstein Campus Kiel
Francesca Zammarchi: ADC Therapeutics (UK) Limited
Daniel-Adriano Silva: University of Washington
K. Christopher Garcia: Stanford University School of Medicine
David Baker: University of Washington
Martin Janz: Max-Delbrück-Center (MDC) for Molecular Medicine
Nikolai Schleussner: Max-Delbrück-Center (MDC) for Molecular Medicine
Falko Fend: Suzanne Turner
Šárka Pospíšilová: Suzanne Turner
Andrea Janiková: Suzanne Turner
Jacqueline Wallwitz: Karl Landsteiner University of Health Sciences
Dagmar Stoiber: Karl Landsteiner University of Health Sciences
Ingrid Simonitsch-Klupp: Medical University of Vienna
Lorenzo Cerroni: Medical University of Graz
Stefano Pileri: European Institute of Oncology IRCCS
Laurence Leval: Lausanne University Hospital (CHUV) and Lausanne University
David Sibon: Université de Paris
Virginie Fataccioli: University Paris East
Philippe Gaulard: University Paris East
Chalid Assaf: HELIOS Hospital Krefeld, Krefeld, Department of Dermatology and Allergy, Charité—Universitätsmedizin Berlin
Fabian Knörr: University Hospital Hamburg-Eppendorf
Christine Damm-Welk: Suzanne Turner
Wilhelm Woessmann: Suzanne Turner
Suzanne D. Turner: Suzanne Turner
A. Thomas Look: Harvard Medical School
Stephan Mathas: Suzanne Turner
Lukas Kenner: Medical University of Vienna
Olaf Merkel: Medical University of Vienna

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25379-9

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