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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, HA. Neubauer, S. Dey, M. Schlederer, BS. Schmalzbauer, T. Limberger, C. Probst, O. Pusch, S. Högler,...
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
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BioMedCentral
from 2002-12-01
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Directory of Open Access Journals
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Free Medical Journals
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PubMed Central
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from 2009-01-01
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- MeSH
- Anaplastic Lymphoma Kinase MeSH
- Lymphoma, Large-Cell, Anaplastic * genetics pathology MeSH
- Phosphorylation MeSH
- Carcinogenesis metabolism MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Receptor, Platelet-Derived Growth Factor beta * metabolism pharmacology MeSH
- Signal Transduction MeSH
- STAT3 Transcription Factor * metabolism MeSH
- STAT5 Transcription Factor * genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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
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 Pathology Medical University of Vienna 1090 Vienna Austria
Department of Pediatric Oncology Dana Farber Cancer Institute Harvard Medical School Boston MA USA
Division of Nuclear Medicine Medical University of Vienna 1090 Vienna Austria
German Cancer Consortium 69120 Heidelberg Germany
Institute of Pathology Charité Medical University of Berlin 10117 Berlin Germany
Institute of Pathology University of Wuerzburg 97080 Würzburg Germany
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
References provided by Crossref.org
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- $a Garces de Los Fayos Alonso, I $u Department of Pathology, Medical University of Vienna, 1090, Vienna, Austria $u Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria
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