Abstract

Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.

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Acknowledgements

GI is supported by the Italian Association for Cancer Research Special Program in Clinical Molecular Oncology, Milan (5 × 1000 No. 10007); Regione Piemonte (ONCOPROT, CIPE 25/2005); ImmOnc (Innovative approaches to boost the immune responses, Programma Operativo Regionale, Piattaforme Innovative BIO FESR 2007/13, Asse 1 ‘Ricerca e innovazione’ della LR 34/2004) and the Oncology Program of Compagnia di San Paolo, Torino. SP and BF are supported by the Italian Association for Cancer Research Special Program in Clinical Molecular Oncology, Milan (5x1000 No. 10007); RR by Partnership for Cure, NIH 1 P50 MH094267-01, NIH 1 U54 CA121852-05, NIH 1R01CA164152-01. FB is sponsored by the Oncosuisse KLS-02403-02-2009 (Bern, Switzerland); Anna Lisa Stiftung (Ascona, Switzerland); Nelia and Amadeo Barletta Foundation (Lausanne, Switzerland); RP by Rete Oncologica del Piemonte e della Valle d’Aosta. LDS is sponsored by National Institutes of Health (USA) grant CA034196. MB, MT, IL, FT FDG, RC and LB are enrolled in the PhD program (Pharmaceutical Sciences, University of Geneva, Switzerland and Molecular Medicine, University of Torino, respectively). We thank Drs Vigliani C, Fioravanti A and Mossino M for their technical support and Dr Casano J for the constructive revision of the manuscript.

Author information

Author notes

    • F Abate
    • , M Todaro
    •  & J-A van der Krogt

    These authors contributed equally to this work.

    • M Cheng

    Current addresses: In Vitro Pharmacology, Merck Research Laboratory, BMB11-138, 33 Avenue Louis Pasteur, Boston, MA 02115.

Affiliations

  1. Department of Control and Computer Engineering, Politecnico di Torino, Turin, Italy

    • F Abate
    • , E Ficarra
    • , A Acquaviva
    •  & R Piva
  2. Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA

    • F Abate
    •  & R Rabadan
  3. Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Turin, Italy

    • F Abate
    • , M Todaro
    • , M Boi
    • , I Landra
    • , R Machiorlatti
    • , F Tabbò
    • , K Messana
    • , C Abele
    • , A Barreca
    • , D Novero
    • , M Gaudiano
    • , S Aliberti
    • , F Di Giacomo
    • , E Lasorsa
    • , R Crescenzo
    • , L Bessone
    •  & G Inghirami
  4. Department of Human Genetics, KU Leuven, Leuven, Belgium

    • J-A van der Krogt
    •  & I Wlodarska
  5. Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland

    • M Boi
    • , A Rinaldi
    • , I Kwee
    •  & F Bertoni
  6. Translational Cell and Tissue Research, KU Leuven, Department of Pathology, UZ Leuven, Leuven, Belgium

    • T Tousseyn
  7. Pathology & Lymphoid Malignancies Units, San Raffaele Scientific Institute, Milan, Italy

    • M Ponzoni
  8. Molecular Imaging Center, Department of Chemistry IFM and Molecular Imaging Center, University of Torino, Turin, Italy

    • D L Longo
    •  & S Aime
  9. Teva Pharmaceuticals, Inc, North Wales, PA, USA

    • M Cheng
    •  & B Ruggeri
  10. Institute of Hematology and Medical Oncology L. and A. Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    • P P Piccaluga
    •  & S Pileri
  11. Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy

    • E Tiacci
    •  & B Falini
  12. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    • B Pera-Gresely
    •  & L Cerchietti
  13. The Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    • J Iqbal
  14. Department of Pathology, City of Hope Medical Center, Duarte, CA, USA

    • W C Chan
  15. The Jackson Laboratory, Bar Harbor, ME, USA

    • L D Shultz
  16. IDSIA Dalle Molle Institute for Artificial Intelligence, Manno, Switzerland

    • I Kwee
  17. SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

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

    • R Piva
    •  & G Inghirami
  19. Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    • F Bertoni
  20. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    • G Inghirami

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The authors declare no conflict of interest.

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Correspondence to R Rabadan or F Bertoni or G Inghirami.

Supplementary information

Appendices

Appendix

Appendix The European T-Cell Lymphoma Study Group:

Italy: Cristina Abele, Luca Bessone, Antonella Barreca, Michela Boi, Federica Cavallo, Nicoletta Chiesa, Ramona Crescenzo, Antonella Fienga, Marcello Gaudiano, Filomena di Giacomo, Giorgio Inghirami, Indira Landra, Elena Lasorsa, Rodolfo Marchiorlatti, Barbara Martinoglio, Enzo Medico, Gian Battista Ferrero, Katia Messana, Elisabetta Mereu, Elisa Pellegrino, Roberto Piva, Irene Scafò, Elisa Spaccarotella, Fabrizio Tabbò, Maria Todaro, Ivana Ubezzi, Susanna Urigu (Azienda Ospedaliera Città della Salute e della Scienza di Torino, University of and Center for Experimental Research and Medical Studies); Domenico Novero, Annalisa Chiapella and Umberto Vitolo (Azienda Ospedaliera Città della Salute e della Scienza di Torino and San Luigi Gonzaga, Turin); Francesco Abate, Elisa Ficarra, Andrea Acquaviva (Politecnico di Torino); Luca Agnelli and Antonino Neri (University of Milan); Anna Caliò Marco Chilosi and Alberto Zamó (University of Verona); Fabio Facchetti and Silvia Lonardi (University of Brescia); Anna De Chiara and Franco Fulciniti (National Cancer Institute, Naples); Andrés Ferreri and Maurilio Ponzoni (San Raffaele Institute, Milan); Claudio Agostinelli, Pier Paolo Piccaluga and Stefano Pileri (University of Bologna); Brunangelo Falini and Enrico Tiacci (University of Perugia). Belgium: Peter Van Loo, Thomas Tousseyn, and Christiane De Wolf-Peeters (University of Leuven); Germany: Eva Geissinger, Hans Konrad Muller-Hermelink and Andreas Rosenwald, (University of Wuerzburg); Spain: Miguel Angel Piris and Maria E. Rodriguez (Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid); Switzerland: Francesco Bertoni, Andrea Rinaldi, Ivo Kwee (Institute of Oncology Research, Bellizona). Brasil: Carlos Chiattone (Disciplina de Hematologia e Oncologia, FCM da Santa Casa de São Paulo) and Roberto Antonio Pinto Paes (Department of Pathology FCM da Santa Casa de São Paulo).

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DOI

https://doi.org/10.1038/leu.2014.347

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

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