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

Claudio Tripodo, Anna Gazzola, Simona Righi, Maria Rosaria Sapienza, Tazzari, Maria Antonella Laginestra, Stefano Aldo Pileri, Fabio Fuligni, Ricci, Bagnara, Rossi, De Renzo, Rossi, Claudio Agostinelli, Went, Pier Paolo Piccaluga, Davide Gibellini, Giorgio Inghirami, Zinzani, ManciniAlviano

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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. © 2014 Macmillan Publishers Limited. All rights reserved.
Lingua originaleEnglish
pagine (da-a)1687-1697
Numero di pagine11
RivistaLeukemia
Volume28
Stato di pubblicazionePublished - 2014

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All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cita questo

Tripodo, C., Gazzola, A., Righi, S., Sapienza, M. R., Tazzari, Laginestra, M. A., Pileri, S. A., Fuligni, F., Ricci, Bagnara, Rossi, De Renzo, Rossi, Agostinelli, C., Went, Piccaluga, P. P., Gibellini, D., Inghirami, G., Zinzani, ... Alviano (2014). Platelet-derived growth factor alpha mediates the proliferation of peripheral T-cell lymphoma cells via an autocrine regulatory pathway. Leukemia, 28, 1687-1697.