Steinhilber Julia, Bonin Michael, Walter Michael, Fend Falko, Bonzheim Irina, Quintanilla-Martinez Leticia
Institute of Pathology and Neuropathology, Tübingen, Germany; Comprehensive Cancer Center, Tübingen, Germany.
Department of Medical Genetics and Applied Genomics, MFT Servives, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany.
PLoS One. 2015 Feb 17;10(2):e0117780. doi: 10.1371/journal.pone.0117780. eCollection 2015.
Anaplastic large cell lymphoma (ALCL) is divided into two systemic diseases according to the expression of the anaplastic lymphoma kinase (ALK). We investigated the differential expression of miRNAs between ALK+ ALCL, ALK- ALCL cells and normal T-cells using next generation sequencing (NGS). In addition, a C/EBPβ-dependent miRNA profile was generated. The data were validated in primary ALCL cases. NGS identified 106 miRNAs significantly differentially expressed between ALK+ and ALK- ALCL and 228 between ALK+ ALCL and normal T-cells. We identified a signature of 56 miRNAs distinguishing ALK+ ALCL, ALK- ALCL and T-cells. The top candidates significant differentially expressed between ALK+ and ALK- ALCL included 5 upregulated miRNAs: miR-340, miR-203, miR-135b, miR-182, miR-183; and 7 downregulated: miR-196b, miR-155, miR-146a, miR-424, miR-503, miR-424*, miR-542-3p. The miR-17-92 cluster was also upregulated in ALK+ cells. Additionally, we identified a signature of 3 miRNAs significantly regulated by the transcription factor C/EBPβ, which is specifically overexpressed in ALK+ ALCL, including the miR-181 family. Of interest, miR-181a, which regulates T-cell differentiation and modulates TCR signalling strength, was significantly downregulated in ALK+ ALCL cases. In summary, our data reveal a miRNA signature linking ALK+ ALCL to a deregulated immune response and may reflect the abnormal TCR antigen expression known in ALK+ ALCL.
间变性大细胞淋巴瘤（ALCL）根据间变性淋巴瘤激酶（ALK）的表达分为两种全身性疾病。我们使用下一代测序（NGS）研究了ALK阳性ALCL、ALK阴性ALCL细胞与正常T细胞之间miRNA的差异表达。此外，还生成了一种依赖C/EBPβ的miRNA谱。这些数据在原发性ALCL病例中得到了验证。NGS鉴定出在ALK阳性和ALK阴性ALCL之间有106种miRNA显著差异表达，在ALK阳性ALCL与正常T细胞之间有228种。我们鉴定出一个由56种miRNA组成的特征，可区分ALK阳性ALCL、ALK阴性ALCL和T细胞。在ALK阳性和ALK阴性ALCL之间显著差异表达的顶级候选miRNA包括5种上调的miRNA：miR-340、miR-203、miR-135b、miR-182、miR-183；以及7种下调的：miR-196b、miR-155、miR-146a、miR-424、miR-503、miR-424*、miR-542-3p。miR-17-92簇在ALK阳性细胞中也上调。此外，我们鉴定出一个由3种受转录因子C/EBPβ显著调控的miRNA组成的特征，该转录因子在ALK阳性ALCL中特异性过表达，包括miR-181家族。有趣的是，调节T细胞分化并调节TCR信号强度的miR-181a在ALK阳性ALCL病例中显著下调。总之，我们的数据揭示了一种将ALK阳性ALCL与失调的免疫反应联系起来的miRNA特征，可能反映了ALK阳性ALCL中已知的异常TCR抗原表达。
