Nat Med. 2012 Oct 14. doi: 10.1038/nm.2966. [Epub ahead of print]
PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.
Laimer D, Dolznig H, Kollmann K, Vesely PW, Schlederer M, Merkel O, Schiefer AI, Hassler MR, Heider S, Amenitsch L, Thallinger C, Staber PB, Simonitsch-Klupp I, Artaker M, Lagger S, Turner SD, Pileri S, Piccaluga PP, Valent P, Messana K, Landra I, Weichhart T, Knapp S, Shehata M, Todaro M, Sexl V, Höfler G, Piva R, Medico E, Ruggeri BA, Cheng M, Eferl R, Egger G, Penninger JM, Jaeger U, Moriggl R, Inghirami G, Kenner L.
1] Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria. [2].
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. |
