Journal
NATURE MEDICINE
Volume 18, Issue 11, Pages 1699-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2966
Keywords
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Funding
- Fonds zur Forderung der wissenschaftlichen Forschung (FWF) [P-18478-B12]
- Genome Research in Austria InflammoBiota project
- FWF [SFB-F28, 19723]
- Elise Richter Fellowship [FWF V102-B12]
- FP7 Marie Curie International Reintegration Grant [IRG 230984]
- Herzfelder Family Foundation
- Niederosterreichische Forschungs- und Bildungsges.m.b.H.P.W.V.
- Jubil umsfonds of the sterreichische Nationalbank [P-12147]
- Else-Kroner Fresenius Stiftung
- Italian Association for Cancer Research (AIRC) Special Program in Clinical Molecular Oncology, Milan [10007]
- Regione Piemonte (ONCOPROT) [CIPE 25/2005]
- ImmOnc ('Innovative approaches to bust the immune responses', Programma Operativo Regionale, Piattaforme Innovative BIO) [LR 34/2004]
- [J 2922]
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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-beta (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.
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