PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.
Nat Med
; 18(11): 1699-704, 2012 Nov.
Article
in En
| MEDLINE
| ID: mdl-23064464
ABSTRACT
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-ß (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein-Tyrosine Kinases
/
Nuclear Proteins
/
Receptor Protein-Tyrosine Kinases
/
Lymphoma, Large-Cell, Anaplastic
/
Receptor, Platelet-Derived Growth Factor alpha
/
Receptor, Platelet-Derived Growth Factor beta
Type of study:
Prognostic_studies
Language:
En
Journal:
Nat Med
Journal subject:
BIOLOGIA MOLECULAR
/
MEDICINA
Year:
2012
Type:
Article
Affiliation country:
Austria