Dal Molin Anna, Hofmans Mattias, Gaffo Enrico, Buratin Alessia, Cavé Hélène, Flotho Christian, de Haas Valerie, Niemeyer Charlotte M, Stary Jan, Van Vlierberghe Pieter, Philippé Jan, De Moerloose Barbara, Te Kronnie Geertruij, Bresolin Silvia, Lammens Tim, Bortoluzzi Stefania
Department of Molecular Medicine, University of Padova, Padua, Italy.
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
Front Cell Dev Biol. 2021 Jan 6;8:613540. doi: 10.3389/fcell.2020.613540. eCollection 2020.
Juvenile myelomonocytic leukemia (JMML), a rare myelodysplastic/myeloproliferative neoplasm of early childhood, is characterized by clonal growth of RAS signaling addicted stem cells. JMML subtypes are defined by specific RAS pathway mutations and display distinct gene, microRNA (miRNA) and long non-coding RNA expression profiles. Here we zoom in on circular RNAs (circRNAs), molecules that, when abnormally expressed, may participate in malignant deviation of cellular processes. CirComPara software was used to annotate and quantify circRNAs in RNA-seq data of a "discovery cohort" comprising 19 JMML patients and 3 healthy donors (HD). In an independent set of 12 JMML patients and 6 HD, expression of 27 circRNAs was analyzed by qRT-PCR. CircRNA-miRNA-gene networks were reconstructed using circRNA function prediction and gene expression data. We identified 119 circRNAs dysregulated in JMML and 59 genes showing an imbalance of the circular and linear products. Our data indicated also circRNA expression differences among molecular subgroups of JMML. Validation of a set of deregulated circRNAs in an independent cohort of JMML patients confirmed the down-regulation of circOXNAD1 and circATM, and a marked up-regulation of circLYN, circAFF2, and circMCTP1. A new finding in JMML links up-regulated circMCTP1 with known tumor suppressor miRNAs. This and other predicted interactions with miRNAs connect dysregulated circRNAs to regulatory networks. In conclusion, this study provides insight into the circRNAome of JMML and paves the path to elucidate new molecular disease mechanisms putting forward circMCTP1 up-regulation as a robust example.
青少年骨髓单核细胞白血病（JMML）是一种罕见的儿童早期骨髓增生异常/骨髓增殖性肿瘤，其特征是对RAS信号成瘾的干细胞发生克隆性生长。JMML亚型由特定的RAS途径突变定义，并表现出不同的基因、微小RNA（miRNA）和长链非编码RNA表达谱。在这里，我们聚焦于环状RNA（circRNA），这些分子在异常表达时可能参与细胞过程的恶性转变。我们使用CirComPara软件对一个由19例JMML患者和3名健康供体（HD）组成的“发现队列”的RNA测序数据中的circRNA进行注释和定量。在另一组由12例JMML患者和6名HD组成的独立样本中，通过qRT-PCR分析了27种circRNA的表达情况。利用circRNA功能预测和基因表达数据重建了circRNA-miRNA-基因网络。我们在JMML中鉴定出119种失调的circRNA和59个显示环状和线性产物失衡的基因。我们的数据还表明JMML分子亚组之间存在circRNA表达差异。在一组独立的JMML患者队列中对一组失调的circRNA进行验证，证实了circOXNAD1和circATM的下调，以及circLYN、circAFF2和circMCTP1的显著上调。JMML中的一项新发现将上调的circMCTP1与已知的肿瘤抑制miRNA联系起来。这种以及其他与miRNA的预测相互作用将失调的circRNA与调控网络联系起来。总之，本研究深入了解了JMML的circRNA组，并为阐明新的分子疾病机制铺平了道路，提出circMCTP1上调就是一个有力的例子。
