Molecular Cancer (Aug 2022)
PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
- I. Garces de los Fayos Alonso,
- L. Zujo,
- I. Wiest,
- P. Kodajova,
- G. Timelthaler,
- S. Edtmayer,
- M. Zrimšek,
- S. Kollmann,
- C. Giordano,
- M. Kothmayer,
- H. A. Neubauer,
- S. Dey,
- M. Schlederer,
- B. S. Schmalzbauer,
- T. Limberger,
- C. Probst,
- O. Pusch,
- S. Högler,
- S. Tangermann,
- O. Merkel,
- A. I. Schiefer,
- C. Kornauth,
- N. Prutsch,
- M. Zimmerman,
- B. Abraham,
- J. Anagnostopoulos,
- L. Quintanilla-Martinez,
- S. Mathas,
- P. Wolf,
- D. Stoiber,
- P. B. Staber,
- G. Egger,
- W. Klapper,
- W. Woessmann,
- T. A. Look,
- P. Gunning,
- S. D. Turner,
- R. Moriggl,
- S. Lagger,
- L. Kenner
Affiliations
- I. Garces de los Fayos Alonso
- Department of Pathology, Medical University of Vienna
- L. Zujo
- Department of Pathology, Medical University of Vienna
- I. Wiest
- Department of Pathology, Medical University of Vienna
- P. Kodajova
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna
- G. Timelthaler
- Center for Cancer Research, Medical University of Vienna
- S. Edtmayer
- Division Pharmacology, Department of Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences
- M. Zrimšek
- Department of Pathology, Medical University of Vienna
- S. Kollmann
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna
- C. Giordano
- Department of Pathology, Medical University of Vienna
- M. Kothmayer
- Department of Pathology, Medical University of Vienna
- H. A. Neubauer
- Institute of Animal Breeding and Genetics, Unit of Functional Cancer Genomics, University of Veterinary Medicine Vienna
- S. Dey
- Department of Dermatology, Medical University of Graz
- M. Schlederer
- Department of Pathology, Medical University of Vienna
- B. S. Schmalzbauer
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna
- T. Limberger
- Department of Pathology, Medical University of Vienna
- C. Probst
- Department of Pathology, Medical University of Vienna
- O. Pusch
- Centre for Anatomy and Cell Biology, Medical University of Vienna
- S. Högler
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna
- S. Tangermann
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna
- O. Merkel
- Department of Pathology, Medical University of Vienna
- A. I. Schiefer
- Department of Pathology, Medical University of Vienna
- C. Kornauth
- Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna
- N. Prutsch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- M. Zimmerman
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- B. Abraham
- Department of Computational Biology, St. Jude Children’s Research Hospital
- J. Anagnostopoulos
- Institute of Pathology, University of Wuerzburg
- L. Quintanilla-Martinez
- Institute of Pathology and Neuropathology and Cluster of excellence iFIT, “Image-Guided and Functionally Instructed Tumor Therapy”, University of Tübingen
- S. Mathas
- Department of Hematology, Oncology, and Cancer Immunology, Charité-Medical University of Berlin
- P. Wolf
- Department of Dermatology, Medical University of Graz
- D. Stoiber
- Division Pharmacology, Department of Pharmacology, Physiology and Microbiology, Karl Landsteiner University of Health Sciences
- P. B. Staber
- Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna
- G. Egger
- Department of Pathology, Medical University of Vienna
- W. Klapper
- Department of Pathology, Hematopathology Section and Lymph Node Registry, University of Kiel/University Hospital Schleswig-Holstein
- W. Woessmann
- Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf
- T. A. Look
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School
- P. Gunning
- Department of Chemical and Physical Sciences, University of Toronto Mississauga
- S. D. Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge
- R. Moriggl
- Institute of Animal Breeding and Genetics, Unit of Functional Cancer Genomics, University of Veterinary Medicine Vienna
- S. Lagger
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna
- L. Kenner
- Department of Pathology, Medical University of Vienna
- DOI
- https://doi.org/10.1186/s12943-022-01640-7
- Journal volume & issue
-
Vol. 21,
no. 1
pp. 1 – 19
Abstract
Abstract 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.
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