title: MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment.
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.
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.|Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Leoncini
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.|Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bertaina
authors.affiliation: Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Papaioannou
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
authors.affiliation: Department of Pediatrics, "Lalla Seràgnoli" Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Masetti
authors.affiliation: Department of Woman and Child Health, Haemato-Oncology Division, University of Padova, Azienda Ospedaliera di Padova, Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bresolin
authors.affiliation: Department of Paediatric Haemato-Oncology, Santobono-Pausilipon Hospital, Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Menna
authors.affiliation: Department of Paediatrics, Paediatric Unit 'F. Vecchio', University of Bari, Bari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.affiliation: Department of Paediatric Haematology and Oncology, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Zecca
authors.affiliation: Department of Woman and Child Health, Haemato-Oncology Division, University of Padova, Azienda Ospedaliera di Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nigita
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA.
authors.forename: Dario
authors.initials: D
authors.lastname: Veneziano
authors.affiliation: Unit of General Pathology, Center of Excellence on Aging and Translational Medicine (CeSI-MeT), G. d'Annunzio University, Chieti, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pagotto
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: D'Ovidio
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Rota
authors.affiliation: Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Dorrance
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.|Department of Paediatric Haematology and Oncology, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D009154:Mutation; D050799:STAT5 Transcription Factor / Q000235:genetics
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D035683:MicroRNAs; D050799:STAT5 Transcription Factor; C533097:MIR150, human; C494095:STAT5B protein, human
keywords: GM-CSF; JMML; STAT5b; miR-150; microRNA