title: Next-generation sequencing identifies deregulation of microRNAs involved in both innate and adaptive immune response in ALK+ ALCL.
abstract: 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.
authors: Institute of Pathology and Neuropathology, Tübingen, Germany; Comprehensive Cancer Center, Tübingen, Germany.
authors: Julia
authors: J
authors: Steinhilber
authors: Department of Medical Genetics and Applied Genomics, MFT Servives, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany.
authors: Michael
authors: M
authors: Bonin
authors: Department of Medical Genetics and Applied Genomics, MFT Servives, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany.
authors: Michael
authors: M
authors: Walter
authors: Institute of Pathology and Neuropathology, Tübingen, Germany; Comprehensive Cancer Center, Tübingen, Germany.
authors: Falko
authors: F
authors: Fend
authors: Institute of Pathology and Neuropathology, Tübingen, Germany; Comprehensive Cancer Center, Tübingen, Germany.
authors: Irina
authors: I
authors: Bonzheim
authors: Institute of Pathology and Neuropathology, Tübingen, Germany; Comprehensive Cancer Center, Tübingen, Germany.
authors: Leticia
authors: L
authors: Quintanilla-Martinez
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases