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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2015

AutorInnen: Merkel, O; Hamacher, F; Griessl, R; Grabner, L; Schiefer, AI; Prutsch, N; Baer, C; Egger, G; Schlederer, M; Krenn, PW; Hartmann, TN; Simonitsch-Klupp, I; Plass, C; Staber, PB; Moriggl, R; Turner, SD; Greil, R; Kenner, L

Titel: Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.

Quelle: J Pathol. 2015; 236(4):445-456

Autor/innen der Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Prutsch Nicole

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik, Abteilung für Funktionelle Krebsgenomik
Institut für Pathologie, Abteilung für Labortierpathologie

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin"s lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).

Keywords Pubmed: Animals
Argonaute Proteins/genetics
Argonaute Proteins/metabolism
CCAAT-Enhancer-Binding Protein-beta/genetics
CCAAT-Enhancer-Binding Protein-beta/metabolism
Case-Control Studies
Caspase 3/metabolism
Cell Line, Tumor
Chromosomes, Human, Pair 2*
Chromosomes, Human, Pair 5*
DNA Methylation
Gene Expression Regulation, Neoplastic
Genetic Therapy/methods
Lymphoma, Large-Cell, Anaplastic/genetics*
Lymphoma, Large-Cell, Anaplastic/metabolism
Lymphoma, Large-Cell, Anaplastic/pathology
Lymphoma, Large-Cell, Anaplastic/therapy
Mice, Inbred NOD
Mice, SCID
Promoter Regions, Genetic
Receptor Protein-Tyrosine Kinases/deficiency
Receptor Protein-Tyrosine Kinases/genetics
STAT3 Transcription Factor/metabolism
Signal Transduction
Suppressor of Cytokine Signaling Proteins/genetics
Suppressor of Cytokine Signaling Proteins/metabolism
Translocation, Genetic*
Xenograft Model Antitumor Assays

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