BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.

Boltzmann Institute Applied Diagnostics 1090 Vienna Austria

CBMed Core Lab Medical University of Vienna 1090 Vienna Austria

Center for Cancer Research Medical University of Vienna 1090 Vienna Austria

Center for Medical Research Medical University of Graz 8010 Graz Austria

Central European Institute of Technology Masaryk University Brno Czech Republic

Centre for Anatomy and Cell Biology Medical University of Vienna 1090 Vienna Austria

Christian Doppler Laboratory of Applied Metabolomics Department of Biomedical Imaging and Image guided Therapy Medical University of Vienna 1090 Vienna Austria

Comprehensive Cancer Center Vienna Vienna General Hospital Medical University of Vienna 1090 Vienna Austria

Department of Chemical and Physical Sciences University of Toronto Mississauga Mississauga ON L5L 1C6 Canada

Department of Chemistry University of Toronto Toronto ON M5S 3H6 Canada

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

Department of Dermatology Medical University of Graz 8036 Graz Austria

Department of Hematology Oncology and Cancer Immunology Charité Medical University of Berlin 12200 Berlin Germany

Department of Medicine 1 Division of Hematology and Hemostaseology Medical University of Vienna 1090 Vienna Austria

Department of Pathology Hematopathology Section and Lymph Node Registry University of Kiel University Hospital Schleswig Holstein 24105 Kiel Germany

Department of Pathology Medical University of Vienna 1090 Vienna Austria

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

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge CB20QQ UK

Division of Nuclear Medicine Medical University of Vienna 1090 Vienna Austria

Division Pharmacology Department of Pharmacology Physiology and Microbiology Karl Landsteiner University of Health Sciences 3500 Krems Austria

Experimental and Clinical Research Center a joint cooperation between the Charité and the MDC 13125 Berlin Germany

German Cancer Consortium 69120 Heidelberg Germany

Institute of Animal Breeding and Genetics Unit of Functional Cancer Genomics University of Veterinary Medicine Vienna 1210 Vienna Austria

Institute of Pathology and Neuropathology and Cluster of excellence iFIT Image Guided and Functionally Instructed Tumor Therapy University of Tübingen 72076 Tübingen Germany

Institute of Pathology Charité Medical University of Berlin 10117 Berlin Germany

Institute of Pathology University of Wuerzburg 97080 Würzburg Germany

Institute of Pharmacology and Toxicology University of Veterinary Medicine Vienna 1210 Vienna Austria

Max Delbrück Center for Molecular Medicine 13125 Berlin Germany

Pediatric Hematology and Oncology University Hospital Hamburg Eppendorf Hamburg Germany

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna 1210 Vienna Austria

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