Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

Department of Computational Biology St Jude Children's Research Hospital Memphis TN 38105 USA

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

Department of Pediatric Oncology Dana Farber Cancer Institute and Boston Children's Hospital Boston MA 02115 USA

Department of Pediatric Oncology Dana Farber Cancer Institute and Boston Children's Hospital Boston MA 02115 USA; Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge MA 02141 USA

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

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge UK; Department of Pediatric Oncology and Hematology Addenbrooke's Hospital Cambridge UK

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge UK; Faculty of Medicine Masaryk University Brno Czech Republic

Division of Molecular Oncology St Jude Children's Research Hospital Memphis TN 38105 USA

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