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

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-memberBATF3andIL-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 followingBATF3knockout, and BATF3 is recruited toIL2Rregulatory 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 patient...

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  64. Department of Biochemistry, University of Washington, Seattle, WA, USA. 19 Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong. 20 Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. 21 Howard Hughes Medical Institute, Chevy Chase, MD, USA. 22 Department of Internal Medicine-Hematology and Oncology, University Hospital Brno, Brno, Czech Republic. 23 Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems, Austria. 24 Department of Dermatology, Medical University of Graz, Graz, Austria. 25 Division of Haematopathology, European Institute of Oncology IRCCS, Milan, Italy. 26 Institute of Pathology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland. 27 Hematology Department, Necker University Hospital, Assistance Publique-Hôpitaux de Paris, and Institut Necker-Enfants Malades, INSERM UMR1151 (Normal and pathological lymphoid differentiation), Université de Paris, Paris, France. 28 Department of Pathology, Henri Mondor University Hospital, AP-HP, INSERM U955, University Paris East, Créteil, France. 29 Department of Dermatology, HELIOS Hospital Krefeld, Krefeld, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany. 30 Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. 31 Center for Biomarker Research in Medicine (CBMed) Core Lab 2, Medical University of Vienna, Vienna, Austria. 32 These authors contributed equally: Stephan Mathas, Lukas Kenner, Olaf Merkel. ✉ email: stephan.mathas@charite.de; lukas.kenner@meduniwien.ac.at; olaf.merkel@meduniwien.ac.at