In-depth characterization of the microRNA transcriptome in a leukemia progression model
In-depth characterization of the microRNA transcriptome in a leukemia progression model
复制标题
DOI：
10.1101/gr.077578.108
复制
发表时间：
2008-11-01
期刊：
影响因子：
7
通讯作者：
Humphries, R. Keith
中科院分区：
文献类型：
--
作者：
Kuchenbauer, Florian;Morin, Ryan D.;Humphries, R. Keith
microRNAs（miRNAs）在包括急性髓性白血病（AML）在内的多种恶性过程中发挥重要作用。为了进一步了解miRNA在AML中的作用，我们应用Illumina大规模并行测序平台对小鼠白血病进展模型中的miRNA转录组进行了深入分析。该模型模拟了通过核孔蛋白98（NUP 98）-同源框HOXD 13融合基因（ND 13）的工程化过表达，在用致癌合作者Meis 1转导后，骨髓祖细胞逐步转化为侵袭性AML诱导细胞。从这个数据集中，我们在ND 13细胞中鉴定了307种miRNA/miRNA*，在ND 13 + Meis 1细胞中鉴定了306种miRNA/miRNA*，对应于223和219个miRNA基因。序列计数在2和136，558之间变化，表明检测到的miRNA种类之间的显著表达范围。大量的miRNA表达和差异表达的性质表明，白血病的进展，如这里所模拟的是由共享的，但差异表达的miRNA的库。我们发现几乎所有的miRNA和miRNA* 物种都存在广泛的序列变异（isomiR），这给miRNA转录组增加了额外的复杂性。严格的靶点预测分析结合体外靶点验证揭示了miRNA介导的癌基因释放的潜力，其促进白血病从白血病前期进展到白血病诱导状态。最后，在我们的数据集中发现了55种新的miRNAs，这进一步增加了新兴的小RNA世界的复杂性。
MicroRNAs ( miRNAs) have been shown to play important roles in physiological as well as multiple malignant processes, including acute myeloid leukemia (AML). In an effort to gain further insight into the role of miRNAs in AML, we have applied the Illumina massively parallel sequencing platform to carry out an in-depth analysis of the miRNA transcriptome in a murine leukemia progression model. This model simulates the stepwise conversion of a myeloid progenitor cell by an engineered overexpression of the nucleoporin 98 (NUP98)-homeobox HOXD13 fusion gene (ND13), to aggressive AML inducing cells upon transduction with the oncogenic collaborator Meis1. From this data set, we identified 307 miRNA/miRNA* species in the ND13 cells and 306 miRNA/miRNA* species in ND13+Meis1 cells, corresponding to 223 and 219 miRNA genes. Sequence counts varied between two and 136,558, indicating a remarkable expression range between the detected miRNA species. The large number of miRNAs expressed and the nature of differential expression suggest that leukemic progression as modeled here is dictated by the repertoire of shared, but differentially expressed miRNAs. Our finding of extensive sequence variations (isomiRs) for almost all miRNA and miRNA* species adds additional complexity to the miRNA transcriptome. A stringent target prediction analysis coupled with in vitro target validation revealed the potential for miRNA-mediated release of oncogenes that facilitates leukemic progression from the preleukemic to leukemia inducing state. Finally, 55 novel miRNAs species were identified in our data set, adding further complexity to the emerging world of small RNAs.