PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma.
Anaplastic Lymphoma Kinase
Animals
Carcinogenesis
/ metabolism
Cell Line, Tumor
Humans
Lymphoma, Large-Cell, Anaplastic
/ genetics
Mice
Phosphorylation
Receptor, Platelet-Derived Growth Factor beta
/ metabolism
STAT3 Transcription Factor
/ metabolism
STAT5 Transcription Factor
/ genetics
Signal Transduction
ALCL
Apoptosis
NPM-ALK
PDGFRβ
STAT3
STAT5A
STAT5B
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
31 08 2022
31 08 2022
Historique:
received:
06
06
2022
accepted:
31
07
2022
entrez:
31
8
2022
pubmed:
1
9
2022
medline:
9
9
2022
Statut:
epublish
Résumé
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-x 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
Sections du résumé
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-x
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
Identifiants
pubmed: 36045346
doi: 10.1186/s12943-022-01640-7
pii: 10.1186/s12943-022-01640-7
pmc: PMC9434917
doi:
Substances chimiques
STAT3 Transcription Factor
0
STAT3 protein, human
0
STAT5 Transcription Factor
0
Anaplastic Lymphoma Kinase
EC 2.7.10.1
Receptor, Platelet-Derived Growth Factor beta
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
172Subventions
Organisme : Austrian Science Fund FWF
ID : I 4066
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : I 4154
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : I 4156
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : P 27132
Pays : Austria
Informations de copyright
© 2022. The Author(s).
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