Oncotarget

Research Papers:

MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment

Pier Paolo Leoncini, Alice Bertaina, Dimitrios Papaioannou, Christian Flotho, Riccardo Masetti, Silvia Bresolin, Giuseppe Menna, Nicola Santoro, Marco Zecca, Giuseppe Basso, Giovanni Nigita, Dario Veneziano, Sara Pagotto, Katia D’Ovidio, Rossella Rota, Adrienne Dorrance, Carlo M. Croce, Charlotte Niemeyer, Franco Locatelli, Ramiro Garzon _

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Oncotarget. 2016; 7:55395-55408. https://doi.org/10.18632/oncotarget.10577

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Abstract

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

Correspondence to:

Ramiro Garzon, email: ramiro.garzon@osumc.edu

Franco Locatelli, email: franco.locatelli@opbg.net

Keywords: JMML, STAT5b, miR-150, microRNA, GM-CSF

Received: April 04, 2016     Accepted: May 13, 2016     Published: July 13, 2016

ABSTRACT

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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