PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F22%3A00128531" target="_blank" >RIV/00216224:14740/22:00128531 - isvavai.cz</a>
Result on the web
<a href="https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01640-7" target="_blank" >https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01640-7</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1186/s12943-022-01640-7" target="_blank" >10.1186/s12943-022-01640-7</a>
Alternative languages
Result language
angličtina
Original language name
PDGFR beta promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
Original language description
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 PDGFR beta. Blocking PDGFR beta 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 PDGFR beta-driven human ALCL in vivo, we identify PDGFR beta as a driver of aggressive tumor growth. Mechanistically, PDGFR beta induces the pro-survival factor Bcl-x(L) 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 PDGFR beta as a novel biomarker and introduce PDGFR beta-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFR beta or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK(+) ALCL patients.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Molecular Cancer
ISSN
1476-4598
e-ISSN
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Volume of the periodical
21
Issue of the periodical within the volume
1
Country of publishing house
GB - UNITED KINGDOM
Number of pages
119
Pages from-to
172
UT code for WoS article
000849356900001
EID of the result in the Scopus database
2-s2.0-85137041648