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PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
University of Veterinary Medicine Vienna / Medical University of Vienna
University of Veterinary Medicine Vienna / Medical University of Vienna
University of Veterinary Medicine Vienna
University of Veterinary Medicine Vienna
S. D. Turner University of Cambridge / Masaryk University
P. Gunning University of Toronto
T. A. Look Harvard Medical School
W. Woessmann University Hospital Hamburg-Eppendorf
W. Klapper University of Kiel
G. Egger Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics
P. B. Staber Medical University of Vienna
D Stoiber Karl Landsteiner University of Health Sciences
P. Wolf Medical University of Graz
S. Mathas Charité-Medical University of Berlin / German Cancer Research Center / Max-Delbrück-Center for Molecular Medicine
L. Quintanilla-Martinez University of Tübingen
J. Anagnostopoulos University of Wuerzburg / Charité-Medical University of Berlin
B. Abraham St. Jude Children's Research Hospital
M. Zimmerman Harvard Medical School
N. Prutsch Harvard Medical School
C. Kornauth Medical University of Vienna
A.I. Schiefer Medical University of Vienna
O. Merkel Medical University of Vienna
S. Tangermann University of Veterinary Medicine Vienna
S. Högler University of Veterinary Medicine Vienna
O Pusch Medical University of Vienna
University of Veterinary Medicine Vienna / Medical University of Vienna
T. Limberger Medical University of Vienna
University of Veterinary Medicine Vienna
M. Schlederer Medical University of Vienna
S. Dey Medical University of Graz
H. A. Neubauer University of Veterinary Medicine Vienna
M. Kothmayer University of Veterinary Medicine Vienna / Medical University of Vienna
C. Giordano Medical University of Vienna
University of Veterinary Medicine Vienna
M. Zrimšek Medical University of Vienna
S. Edtmayer Karl Landsteiner University of Health Sciences
G. Timelthaler Medical University of Vienna
P. Kodajova University of Veterinary Medicine Vienna
L. Zujo University of Veterinary Medicine Vienna / Medical University of Vienna
I. West University of Veterinary Medicine Vienna / Medical University of Vienna
BMC
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.
English
2022
This work is licensed under a
CC BY 4.0 - Creative Commons Attribution 4.0 International License.
CC BY 4.0 International
http://creativecommons.org/licenses/by/4.0/
Npm-Alk; Dna Methylation; Gene-Expression; Cancer; Chemotherapy; Differentiation; Stat3; Children; Therapy; Safety