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

Author

Listed:
  • Huan-Chang Liang

    (Medical University of Vienna
    Suzanne Turner)

  • Mariantonia Costanza

    (Suzanne Turner
    Max-Delbrück-Center (MDC) for Molecular Medicine
    Department of Hematology, Oncology, and Cancer Immunology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, and Experimental and Clinical Research Center (ECRC), a joint cooperation between the MDC and Charité)

  • Nicole Prutsch

    (Harvard Medical School)

  • Mark W. Zimmerman

    (Harvard Medical School)

  • Elisabeth Gurnhofer

    (Medical University of Vienna)

  • Ivonne A. Montes-Mojarro

    (Suzanne Turner
    University Hospital and Comprehensive Cancer Center Tübingen)

  • Brian J. Abraham

    (St. Jude Children’s Research Hospital)

  • Nina Prokoph

    (Suzanne Turner
    University of Cambridge, Addenbrooke’s Hospital)

  • Stefan Stoiber

    (Medical University of Vienna
    Medical University of Vienna)

  • Simone Tangermann

    (University of Veterinary Medicine Vienna)

  • Cosimo Lobello

    (Suzanne Turner
    Masaryk University)

  • 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
    University of Washington
    The Hong Kong University of Science and Technology)

  • K. Christopher Garcia

    (Stanford University School of Medicine
    Howard Hughes Medical Institute)

  • David Baker

    (University of Washington
    University of Washington
    Howard Hughes Medical Institute)

  • Martin Janz

    (Max-Delbrück-Center (MDC) for Molecular Medicine
    Department of Hematology, Oncology, and Cancer Immunology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, and Experimental and Clinical Research Center (ECRC), a joint cooperation between the MDC and Charité)

  • Nikolai Schleussner

    (Max-Delbrück-Center (MDC) for Molecular Medicine
    Department of Hematology, Oncology, and Cancer Immunology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, and Experimental and Clinical Research Center (ECRC), a joint cooperation between the MDC and Charité)

  • Falko Fend

    (Suzanne Turner
    University Hospital and Comprehensive Cancer Center Tübingen)

  • Šárka Pospíšilová

    (Suzanne Turner
    Masaryk University
    University Hospital Brno)

  • Andrea Janiková

    (Suzanne Turner
    University Hospital Brno)

  • 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
    University Hospital Hamburg-Eppendorf)

  • Wilhelm Woessmann

    (Suzanne Turner
    University Hospital Hamburg-Eppendorf)

  • Suzanne D. Turner

    (Suzanne Turner
    University of Cambridge, Addenbrooke’s Hospital
    Masaryk University)

  • A. Thomas Look

    (Harvard Medical School)

  • Stephan Mathas

    (Suzanne Turner
    Max-Delbrück-Center (MDC) for Molecular Medicine
    Department of Hematology, Oncology, and Cancer Immunology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, and Experimental and Clinical Research Center (ECRC), a joint cooperation between the MDC and Charité
    German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ))

  • Lukas Kenner

    (Medical University of Vienna
    Suzanne Turner
    Medical University of Vienna
    University of Veterinary Medicine Vienna)

  • Olaf Merkel

    (Medical University of Vienna
    Suzanne Turner)

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.

Suggested Citation

  • 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 & C, 2021. "Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25379-9
    DOI: 10.1038/s41467-021-25379-9
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