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

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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Figure 1: Effects of JUN and JUNB deletion on NPM-ALK lymphomas in mice.
Figure 2: PDGFRB is a direct transcriptional target of JUNB and JUN.
Figure 3: PDFGR inhibition interferes with formation of transplanted tumors.
Figure 4: Complete remission of ALCL in a patient after imatinib treatment.

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Acknowledgements

We thank E.F. Wagner for providing the JUNBflox/flox and JUNflox/flox mice, A. Ostman for helpful discussions and technical help with PDGFRB analysis, and S. Reichmann for technical help with soluble-CD30 and PDGFB assays. L.K. is supported by the Fonds zur Förderung der wissenschaftlichen Forschung (FWF, P-18478-B12) and the Genome Research in Austria InflammoBiota project. R.M., V.S. and R.E. are supported by the FWF (SFB-F28) and V.S. is supported by FWF project 19723. G.E. is supported by an Elise Richter Fellowship (FWF V102-B12) and an FP7 Marie Curie International Reintegration Grant (IRG 230984). H.D. is supported by the Herzfelder Family Foundation and the Niederösterreichische Forschungs- und Bildungsges.m.b.H. P.W.V. and P.B.S. were supported by Jubiläumsfonds of the Österreichische Nationalbank (P-12147), and P.W.V. was awarded an E. Schroedinger Grant (J 2922). T.W. is supported by the Else-Kröner Fresenius Stiftung. S.P. and G.I. are supported by Italian Association for Cancer Research (AIRC) Special Program in Clinical Molecular Oncology, Milan (5x1000 No. 10007). G.I. is supported by Regione Piemonte (ONCOPROT, CIPE 25/2005); ImmOnc ('Innovative approaches to bust the immune responses', Programma Operativo Regionale, Piattaforme Innovative BIO F.E.S.R. 2007/13, Asse 1 'Ricerca e innovazione' della LR 34/2004) and the Oncology Program of Compagnia di San Paolo, Torino. R.P. is supported by AIRC grant IG-8675. R.E. is supported by the FWF Doktoratskolleg-plus Inflammation and Immunity grant, the Comprehensive Cancer Center Vienna Research Grant and the Austrian Federal Ministry of Science and Research GENAU Austromouse grant. J.M.P. is supported by the Austrian Academy of Sciences and an Advanced Grant from the European Research Council. This study was performed on behalf of the European Research Initiative on ALCL (ERIA).

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H.D., P.W.V., K.K., O.M., P.V., T.W., M. Shehata, V.S., G.H., G.E., J.M.P., U.J., R.M., G.I., R.E. and L.K. designed experiments. D.L., H.D., K.K., P.W.V., M. Schlederer, O.M., A.-I.S., M.R.H., S.H., L.A., C.T., P.B.S., I.S.-K., M.A., S.P., P.P.P., K.M., I.L., S.K., M. Shehata, M.T., S.L., S.D.T., R.P., E.M., G.E., R.M., M.C. and B.A.R. performed experiments and collected and analyzed data. H.D., V.S., R.M., J.M.P., G.I., R.E. and L.K. wrote the manuscript. All authors discussed the results and edited the manuscript.

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Correspondence to Lukas Kenner.

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Supplementary Case Report, Supplementary Methods, Supplementary Figs. 1–8 (PDF 1297 kb)

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Laimer, D., Dolznig, H., Kollmann, K. et al. PDGFR blockade is a rational and effective therapy for NPM-ALK–driven lymphomas. Nat Med 18, 1699–1704 (2012). https://doi.org/10.1038/nm.2966

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