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PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.

Authors
  • Laimer, Daniela
  • Dolznig, Helmut
  • Kollmann, Karoline
  • Vesely, Paul W
  • Schlederer, Michaela
  • Merkel, Olaf
  • Schiefer, Ana-Iris
  • Hassler, Melanie R
  • Heider, Susi
  • Amenitsch, Lena
  • Thallinger, Christiane
  • Staber, Philipp B
  • Simonitsch-Klupp, Ingrid
  • Artaker, Matthias
  • Lagger, Sabine
  • Turner, Suzanne D
  • Pileri, Stefano
  • Piccaluga, Pier Paolo
  • Valent, Peter
  • Messana, Katia
  • And 18 more
Type
Published Article
Journal
Nature medicine
Publication Date
Nov 01, 2012
Volume
18
Issue
11
Pages
1699–1704
Identifiers
DOI: 10.1038/nm.2966
PMID: 23064464
Source
Medline
License
Unknown

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-β (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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