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

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.

• Authors: 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, S A Pileri
• Journal: Leukemia (Leukemia) Vol. 28 Issue 8 Pg. 1687-97 (Aug 2014) ISSN: 1476-5551 [Electronic] England
• PMID: 24480986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Platelet-Derived Growth Factor
• STAT1 Transcription Factor
• STAT1 protein, human
• STAT5 Transcription Factor
• platelet-derived growth factor A
• Receptor, Platelet-Derived Growth Factor alpha
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Autocrine Communication
• Cell Line, Tumor
• Cell Proliferation
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Humans
• Lymphoma, T-Cell, Peripheral (pathology)
• Platelet-Derived Growth Factor (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Receptor, Platelet-Derived Growth Factor alpha (genetics, physiology)
• STAT1 Transcription Factor
• STAT5 Transcription Factor (physiology)