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Lymphoma

Platelet-derived growth factor alpha mediates the proliferation of peripheral T-cell lymphoma cells via an autocrine regulatory pathway

Leukemia volume 28, pages 1687–1697 (2014)Cite this article

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Abstract

Peripheral T-cell lymphomas not otherwise specified (PTCL/NOS) are very aggressive tumors characterized by consistent aberrant expression of platelet-derived growth factor receptor alpha (PDGFRA). In this study, we aimed to identify the determinants of PDGFRA activity in PTCL/NOS and to elucidate the biological consequences of its activation. We observed overexpression of the PDGFRA gene by gene expression profiling in most of the tested PTCLs and confirmed the expression of PDGFRA and phospho-PDGFRA using immunohistochemistry. The integrity of the PDFGRA locus was demonstrated using several different approaches, including massive parallel sequencing and Sanger sequencing. PDGF-AA was found to be expressed and secreted by PTCL/NOS cells and to be necessary and sufficient for PDGFRA phosphorylation ex vivo by sustaining an autocrine stimulation. We documented consistently high PDGF-A expression in primary biopsies and patients’ plasma and tracked PDGFRA signaling in primary tumors, achieving evidence of its activation. Indeed, we found that STAT1 and STAT5 are implicated in PDGFRA signaling transduction. Finally, we demonstrated that PDGFRA activation supported tumor cell proliferation and provided the first evidence of the anti-lymphoma activity of PDGRA inhibition in a PTCL/NOS patient. Altogether, our data demonstrated that PDGFRA activity fosters PTCL/NOS proliferation via an autocrine loop.

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Acknowledgements

We are grateful to Dr Aurora Esposito for her technical assistance. This work was supported by the Centro Interdipartimentale per la Ricerca sul Cancro ‘G. Prodi’, BolognAIL, AIRC (IG4987; IG10519; 10007 5xMille; IG 2013N.14355), RFO (Prof Pileri and Prof Piccaluga), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, Progetto Strategico di Ateneo 2006 (Prof Pileri and Prof Piccaluga), and FIRB Futura 2011 RBFR12D1CB (Prof Piccaluga).

Author information

Author notes

  1. P P Piccaluga, M Rossi, C Agostinelli, F Ricci, A Gazzola, S Righi, F Fuligni, M A Laginestra, M Mancini, M R Sapienza, A De Renzo, P L Tazzari, D Gibellini, P Went, F Alviano, P L Zinzani, G P Bagnara, G Inghirami, C Tripodo and S A Pileri: P P Piccaluga and M Rossi: These authors contributed equally to this work.

  2. See Appendix.

Authors and Affiliations

  1. Department of Experimental, Hematopathology Section, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy

    P P Piccaluga, M Rossi, C Agostinelli, A Gazzola, S Righi, F Fuligni, M A Laginestra, M R Sapienza & S A Pileri

  2. Transfusion Medicine Service, S. Orsola-Malpighi Hospital, Bologna, Italy

    F Ricci & P L Tazzari

  3. Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Bologna, Italy

    M Mancini, F Alviano, P L Zinzani & G P Bagnara

  4. Ematologia Università ‘Federico II’, Napoli, Italy

    A De Renzo

  5. Department of Experimental, Microbiology Section, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy

    D Gibellini

  6. Institute of Pathology, Basel, Switzerland

    P Went

  7. Department of Pathology and Center for Experimental Research and Medical Studies, University of Torino, Turin, Italy

    G Inghirami

  8. Dipartimento di Scienze per la Promozione della Salute, Sezione di Anatomia Patologica, Università degli Studi di Palermo, Palermo, Italy

    C Tripodo

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on behalf of the AIRC 5xMille consortium ‘Genetics-driven targeted management of lymphoid malignancies’ and the European T-cell Lymphoma Study Group

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Correspondence to P P Piccaluga.

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Supplementary Information accompanies this paper on the Leukemia website

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Appendix

Appendix

AIRC 5xMille consortium ‘Genetics-driven targeted management of lymphoid malignancies’: Robin Foà, Sabina Chiaretti, Filippo Berardelli, Brunangelo Falini, Enrico Tiacci, Giorgio Inghirami, Roberto Piva, Gianluca Gaidano, Davide Rossi, Stefano Pileri and Pier Paolo Piccaluga.

The European T-Cell Lymphoma Study Group: Italy: Giorgio Inghirami and Roberto Piva, (Azienda Ospedaliera Città della Salute e della Scienza di Torino, University of Torino); 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, Napoli); Claudio Doglioni, Andrés Ferreri and Maurilio Ponzoni (San Raffaele Institute, Milano); Claudio Agostinelli, Pier Paolo Piccaluga and Stefano Pileri (University of Bologna); Brunangelo Falini, Stefano Ascani, and Enrico Tiacci (University of Perugia); Belgium: Peter Van Loo, Thomas Tousseyn, and Christiane De Wolf-Peeters (University of Leuven); Germany: Eva Geissinger and Andreas Rosenwald, (University of Wuerzburg); Martin Leo Hansmann and Sylvia Hartmann (University of Frankfurt); 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).

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Piccaluga, P., Rossi, M., Agostinelli, C. et al. Platelet-derived growth factor alpha mediates the proliferation of peripheral T-cell lymphoma cells via an autocrine regulatory pathway. Leukemia 28, 1687–1697 (2014). https://doi.org/10.1038/leu.2014.50

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