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Type of publication: Journal Article
Type of document: Full Paper

Year: 2015

Authors: 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

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

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

Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Prutsch Nicole

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics

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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