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

Nature Medicine volume 18, pages 1699–1704 (2012)Cite this article

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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).

Author information

Author notes

  1. Paul W Vesely, Olaf Merkel & Sabine Lagger

    Present address: Present addresses: The Scripps Research Institute, La Jolla, California (P.W.V.), National Center for Tumor Diseases, Heidelberg, Germany (O.M.) and Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK (S.L.).,

  2. Daniela Laimer, Helmut Dolznig, Karoline Kollmann and Paul W Vesely: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

    Daniela Laimer, Ana-Iris Schiefer, Melanie R Hassler, Susi Heider, Lena Amenitsch, Ingrid Simonitsch-Klupp, Gerda Egger & Lukas Kenner

  2. Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria

    Helmut Dolznig & Thomas Weichhart

  3. Institute of Pharmacology and Toxicology, Veterinary University Vienna, Vienna, Austria

    Karoline Kollmann & Veronika Sexl

  4. Institute of Pathology, Medical University of Graz, Graz, Austria

    Paul W Vesely & Gerald Höfler

  5. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    Michaela Schlederer, Richard Moriggl & Lukas Kenner

  6. 3rd Medical Department of the Paracelsus Medical University, Laboratory for Immunological and Molecular Cancer Research, Salzburg, Austria

    Olaf Merkel

  7. Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria

    Melanie R Hassler & Christiane Thallinger

  8. Division of Hematology, Medical University of Graz, Graz, Austria

    Philipp B Staber

  9. Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA

    Philipp B Staber

  10. Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna Biocenter, Vienna, Austria.,

    Matthias Artaker & Sabine Lagger

  11. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

    Suzanne D Turner

  12. Department of Hematology and Oncology 'L. and A. Seràgnoli,' S. Orsola-Malpighi Hospital, Pathology and Hematopathology Unit, University of Bologna, Bologna, Italy

    Stefano Pileri & Pier Paolo Piccaluga

  13. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Comprehensive Cancer Center Drug & Target Screening Unit, Medical University of Vienna, Vienna, Austria

    Peter Valent, Medhat Shehata & Ulrich Jaeger

  14. Ludwig Boltzmann Cluster Oncology, Vienna, Austria

    Peter Valent

  15. Department of Molecular Biotechnology and Health Science, Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy

    Katia Messana, Indira Landra, Maria Todaro, Roberto Piva & Giorgio Inghirami

  16. Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Sylvia Knapp

  17. Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria

    Sylvia Knapp

  18. Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, New York, USA

    Roberto Piva

  19. Department of Oncological Sciences, University of Turin, Turin, Italy

    Enzo Medico & Giorgio Inghirami

  20. Laboratory of Oncogenomics, Institute for Cancer Research and Treatment, Candiolo, Italy

    Enzo Medico

  21. Worldwide Discovery Research, Cephalon, Inc., West Chester, Pennsylvania, USA

    Bruce A Ruggeri & Mangeng Cheng

  22. Department of Internal Medicine I, Institute for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Robert Eferl

  23. Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, Austria

    Josef M Penninger

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  1. Daniela Laimer
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Contributions

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.

Corresponding author

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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