MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment
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Pier Paolo Leoncini1,11,*, Alice Bertaina1,11,*, Dimitrios Papaioannou2, Christian Flotho3, Riccardo Masetti4, Silvia Bresolin5, Giuseppe Menna6, Nicola Santoro7, Marco Zecca8, Giuseppe Basso5, Giovanni Nigita9, Dario Veneziano9, Sara Pagotto10, Katia D’Ovidio1, Rossella Rota1, Adrienne Dorrance2, Carlo M. Croce9, Charlotte Niemeyer3, Franco Locatelli1,8, Ramiro Garzon2
1Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children’s Hospital, Rome, Italy
2Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
3Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany
4Department of Pediatrics, “Lalla Seràgnoli” Hematology-Oncology Unit, University of Bologna, Bologna, Italy
5Department of Woman and Child Health, Haemato-Oncology Division, University of Padova, Azienda Ospedaliera di Padova, Padova, Italy
6Department of Paediatric Haemato-Oncology, Santobono-Pausilipon Hospital, Napoli, Italy
7Department of Paediatrics, Paediatric Unit 'F. Vecchio', University of Bari, Bari, Italy
8Department of Paediatric Haematology and Oncology, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy
9Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA
10Unit of General Pathology, Center of Excellence on Aging and Translational Medicine (CeSI-MeT), G. d’Annunzio University, Chieti, Italy
11Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, Chieti, Italy
*These authors have contributed equally to this work
Ramiro Garzon, email: [email protected]
Franco Locatelli, email: [email protected]
Keywords: JMML, STAT5b, miR-150, microRNA, GM-CSF
Received: April 04, 2016 Accepted: May 13, 2016 Published: July 13, 2016
Juvenile myelomonocytic leukemia (JMML) is an aggressive leukemia of early childhood characterized by aberrant proliferation of myelomonocytic cells and hypersensitivity to GM-CSF stimulation. Mutually exclusive mutations in the RAS/ERK pathway genes such as PTPN11, NRAS, KRAS, CBL, or NF1 are found in ~90% of the cases. These mutations give rise to disease at least in part by activating STAT5 through phosphorylation and by promoting cell growth. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression, which are often deregulated in leukemia. However, little is known about their role in JMML. Here, we report distinctive miR expression signatures associated with the molecular subgroups of JMML. Among the downregulated miRs in JMML, miR-150-5p was found to target STAT5b, a gene which is often over-activated in JMML, and contributes to the characteristic aberrant signaling of this disorder. Moreover, loss of miR-150-5p and upregulation of STAT5b expression were also identified in a murine model of JMML. Ectopic overexpression of miR-150-5p in mononuclear cells from three JMML patients significantly decreased cell proliferation. Altogether, our data indicate that miR expression is deregulated in JMML and may play a role in the pathogenesis of this disorder by modulating key effectors of cytokine receptor pathways.
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