Leoncini Pier Paolo, Bertaina Alice, Papaioannou Dimitrios, Flotho Christian, Masetti Riccardo, Bresolin Silvia, Menna Giuseppe, Santoro Nicola, Zecca Marco, Basso Giuseppe, Nigita Giovanni, Veneziano Dario, Pagotto Sara, D'Ovidio Katia, Rota Rossella, Dorrance Adrienne, Croce Carlo M, Niemeyer Charlotte, Locatelli Franco, Garzon Ramiro
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.
Oncotarget. 2016 Aug 23;7(34):55395-55408. doi: 10.18632/oncotarget.10577.
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.
青少年粒单核细胞白血病（JMML）是一种儿童早期侵袭性白血病，其特征为粒单核细胞异常增殖以及对粒细胞-巨噬细胞集落刺激因子（GM-CSF）刺激超敏。约90%的病例中可发现RAS/ERK通路基因如PTPN11、NRAS、KRAS、CBL或NF1存在相互排斥的突变。这些突变至少部分通过磷酸化激活信号转导和转录激活因子5（STAT5）以及促进细胞生长而引发疾病。微小RNA（miR）是调节基因表达的小非编码RNA，在白血病中常发生失调。然而，其在JMML中的作用知之甚少。在此，我们报告了与JMML分子亚组相关的独特miR表达特征。在JMML中下调的miR中，发现miR-150-5p靶向STAT5b，该基因在JMML中常过度激活，并促成了这种疾病的特征性异常信号传导。此外，在JMML小鼠模型中也鉴定出miR-150-5p缺失和STAT5b表达上调。在三名JMML患者的单核细胞中异位过表达miR-1 five zero five p显著降低了细胞增殖。总之，我们的数据表明miR表达在JMML中失调，并可能通过调节细胞因子受体途径的关键效应因子在这种疾病的发病机制中发挥作用。
