o:2106 PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma en 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.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.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. Npm-Alk; Dna Methylation; Gene-Expression; Cancer; Chemotherapy; Differentiation; Stat3; Children; Therapy; Safety 1552099 10.1186/s12943-022-01640-7 2023-09-18T14:32:24.521Z 44 yes 46 I. Garces de Los Fayos Alonso University of Veterinary Medicine Vienna / Medical University of Vienna 0000-0002-0187-4194 L. Zujo University of Veterinary Medicine Vienna / Medical University of Vienna person I. West University of Veterinary Medicine Vienna / Medical University of Vienna person P. Kodajova University of Veterinary Medicine Vienna person G. Timelthaler Medical University of Vienna person S. Edtmayer Karl Landsteiner University of Health Sciences person M. Zrimšek Medical University of Vienna person S. Kollmann University of Veterinary Medicine Vienna person 0000-0001-7911-9896 C. Giordano Medical University of Vienna person M. Kothmayer University of Veterinary Medicine Vienna / Medical University of Vienna person H. A. Neubauer University of Veterinary Medicine Vienna person S. Dey Medical University of Graz person M. Schlederer Medical University of Vienna person B. S. Schmalzbauer University of Veterinary Medicine Vienna person 0000-0002-1881-0883 T. Limberger Medical University of Vienna person C. Probst University of Veterinary Medicine Vienna / Medical University of Vienna person 0000-0001-9247-7508 O Pusch Medical University of Vienna person S. Högler University of Veterinary Medicine Vienna person S. Tangermann University of Veterinary Medicine Vienna person O. Merkel Medical University of Vienna person A.I. Schiefer Medical University of Vienna person C. Kornauth Medical University of Vienna person N. Prutsch Harvard Medical School person M. Zimmerman Harvard Medical School person B. Abraham St. Jude Children's Research Hospital person J. Anagnostopoulos University of Wuerzburg / Charité-Medical University of Berlin person L. Quintanilla-Martinez University of Tübingen person S. Mathas Charité-Medical University of Berlin / German Cancer Research Center / Max-Delbrück-Center for Molecular Medicine person P. Wolf Medical University of Graz person D Stoiber Karl Landsteiner University of Health Sciences person P. B. Staber Medical University of Vienna person G. Egger Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics person W. Klapper University of Kiel person W. Woessmann University Hospital Hamburg-Eppendorf person T. A. Look Harvard Medical School person P. Gunning University of Toronto person S. D. Turner University of Cambridge / Masaryk University person R. Moriggl University of Veterinary Medicine Vienna person 0000-0003-0918-9463 S. Lagger University of Veterinary Medicine Vienna person 0000-0002-3032-9910 L. Kenner University of Veterinary Medicine Vienna / Medical University of Vienna person 0000-0003-2184-1338 application/pdf 2393132 https://phaidra.vetmeduni.ac.at/o:2106 no yes 16 70 1552253 Molecular Cancer 19 21 1 BMC 2022