MYCN is a novel oncogenic target in pediatric T-cell Acute Lymphoblastic Leukemia

// Annalisa Astolfi 1,2 , Francesca Vendemini 2 , Milena Urbini 1,2 , Fraia Melchionda 2 , Riccardo Masetti 2 , Monica Franzoni 2 , Virginia Libri 2 , Salvatore Serravalle 2 , Marco Togni 2 , Giuseppina Paone 2 , Luca Montemurro 2 ,Daniela Bressanin 3 , Francesca Chiarini 4 , Alberto M. Martelli 3 , Roberto Tonelli 5 , Andrea Pession 1,2 1 “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna, Italy; 2 Pediatric Oncology and Hematology Unit “Lalla Seragnoli”, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; 3 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 4 Institute of Molecular Genetics, National Research Council-IOR, Bologna, Italy; 5 Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. Correspondence: Riccardo Masetti, email: // Keywords : pediatric T-ALL, MYCN, peptide nucleic acid, TAL1 Received : August 28, 2013 Accepted : September 27, 2013 Published : September 29, 2013 Abstract MYCN is an oncogene frequently overexpressed in pediatric solid tumors whereas few evidences suggest his involvement in the pathogenesis of haematologic malignancies. Here we show that MYCN is overexpressed in a relevant proportion (40 to 50%) of adult and pediatric T-cell acute lymphoblastic leukemias (T-ALL). Focusing on pediatric T-ALL, MYCN-expressing samples were found almost exclusively in the TAL1-positive subgroup. Moreover, TAL1 knockdown in T-ALL cell lines resulted in a reduction of MYCN expression, and TAL1 directly binds to MYCN promoter region, suggesting that TAL1 pathway activation could sustain the up-regulation of MYCN. The role of MYCN in T-ALL was investigated by peptide nucleic acid (PNA-MYCN)-mediated transcriptional silencing of MYCN and by siRNAs. MYCN knockdown in T-ALL cell lines resulted in a reduction of cell viability, up to 50%, while no effect was elicited with a mismatch PNA. The inhibitory effect of PNA-MYCN on cell viability was due to a significant increase in apoptosis. PNA-MYCN treatment in pediatric T-ALL samples reduced cell viability of leukemic cells from patients with high MYCN expression, while no effect was obtained in MYCN-negative blast cells. These results showed that MYCN is frequently overexpressed in pediatric T-ALL and suggested his role as a candidate for molecularly-directed therapies.