Next-generation sequencing identifies deregulation of microRNAs involved in both innate and adaptive immune response in ALK+ ALCL

PLoS One. 2015 Feb 17;10(2):e0117780. doi: 10.1371/journal.pone.0117780. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics*
  • Anaplastic Lymphoma Kinase
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunity, Innate / genetics*
  • Lymphoma, Large-Cell, Anaplastic / genetics
  • Lymphoma, Large-Cell, Anaplastic / immunology*
  • Lymphoma, Large-Cell, Anaplastic / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • MicroRNAs
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases

Grant support

This work was supported by the SFB 685 “Immunotherapy” of the University of Tübingen, TP B8 (LQM and FF, http://www.sfb685.de/) and by the IZKF fortüne program (1924-0-0), University of Tübingen (IB, https://www.medizin.uni-tuebingen.de/Forschung/Forschungsf%C3%B6rderung/Interne+Forschungsf%C3%B6rderung/fort%C3%BCne.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.