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

HC. Liang, M. Costanza, N. Prutsch, MW. Zimmerman, E. Gurnhofer, IA. Montes-Mojarro, BJ. Abraham, N. Prokoph, S. Stoiber, S. Tangermann, C. Lobello, J. Oppelt, I. Anagnostopoulos, T. Hielscher, S. Pervez, W. Klapper, F. Zammarchi, DA. Silva, KC....

. 2021 ; 12 (1) : 5577. [pub] 20210922

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22003692

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.

ADC Therapeutics Limited London UK

Center for Biomarker Research in Medicine Core Lab 2 Medical University of Vienna Vienna Austria

Central European Institute of Technology Masaryk University Brno Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department of Biochemistry University of Washington Seattle WA USA

Department of Computational Biology St Jude Children's Research Hospital Memphis TN USA

Department of Dermatology HELIOS Hospital Krefeld Krefeld Department of Dermatology and Allergy Charité Universitätsmedizin Berlin Berlin Germany

Department of Dermatology Medical University of Graz Graz Austria

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 a joint cooperation between the MDC and Charité Berlin Germany

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Pathology and Laboratory Medicine Aga Khan University Hospital Karachi Pakistan

Department of Pathology Hematopathology Section University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Pathology Henri Mondor University Hospital AP HP INSERM U955 University Paris East Créteil France

Department of Pathology Unit of Experimental and Laboratory Animal Pathology Medical University of Vienna Vienna Austria

Department of Pediatric Oncology Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Pharmacology Physiology and Microbiology Division Pharmacology Karl Landsteiner University of Health Sciences Krems Austria

Departments of Molecular and Cellular Physiology and Structural Biology Stanford University School of Medicine Stanford CA USA

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge UK

Division of Haematopathology European Institute of Oncology IRCCS Milan Italy

Division of Life Science The Hong Kong University of Science and Technology Kowloon Hong Kong

European Research Initiative on ALK Related Malignancies Suzanne Turner Cambridge UK

German Cancer Consortium Heidelberg Germany

Group Biology of Malignant Lymphomas Max Delbrück Center for Molecular Medicine Berlin Germany

Hematology Department Necker University Hospital Assistance Publique Hôpitaux de Paris and Institut Necker Enfants Malades INSERM UMR1151 Université de Paris Paris France

Howard Hughes Medical Institute Chevy Chase MD USA

Institute for Protein Design University of Washington Seattle WA USA

Institute of Pathology and Neuropathology University Hospital and Comprehensive Cancer Center Tübingen Tübingen Germany

Institute of Pathology Lausanne University Hospital and Lausanne University Lausanne Switzerland

Institute of Pathology University of Würzburg Würzburg Germany

Pediatric Hematology and Oncology University Hospital Hamburg Eppendorf Hamburg Germany

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

Citace poskytuje Crossref.org

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$a 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.
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