Platelet-derived growth factor alpha mediates the proliferation of peripheral T-cell lymphoma cells via an autocrine regulatory pathway.
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.
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Piccaluga
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Rossi
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Agostinelli
Transfusion Medicine Service, S. Orsola-Malpighi Hospital, Bologna, Italy.
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Ricci
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Gazzola
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Righi
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Fuligni
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Laginestra
Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Bologna, Italy.
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Mancini
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Sapienza
Ematologia Università 'Federico II', Napoli, Italy.
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De Renzo
Transfusion Medicine Service, S. Orsola-Malpighi Hospital, Bologna, Italy.
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Tazzari
Microbiology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Gibellini
Institute of Pathology, Basel, Switzerland.
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Went
Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Bologna, Italy.
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Alviano
Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Bologna, Italy.
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Zinzani
Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University Medical School, Bologna, Italy.
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Bagnara
Department of Pathology and Center for Experimental Research and Medical Studies, University of Torino, Turin, Italy.
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Inghirami
Dipartimento di Scienze per la Promozione della Salute, Sezione di Anatomia Patologica, Università degli Studi di Palermo, Palermo, Italy.
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Tripodo
Hematopathology Section, Department of Experimental, Diagnostic, and Specialty Medicine, S. Orsola-Malpighi Hospital, Bologna University Medical School, Bologna, Italy.
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Pileri
D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D016411:Lymphoma, T-Cell, Peripheral / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor / Q000502:physiology
D010982:Platelet-Derived Growth Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases