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J Pathol. 2015 Aug;236(4):445-56. doi: 10.1002/path.4539. Epub 2015 Apr 27.

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

Author information

1
Department of Translational Oncology, National Centre for Tumour Diseases (NCT), German Cancer Research Centre (DKFZ), Heidelberg, Germany.
2
Department of Clinical Pathology, Medical University Vienna, Austria.
3
European Research Initiative on ALK Related Malignancies (www.erialcl.net).
4
Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Oncologic Centre, Paracelsus Medical University, Salzburg, Austria.
5
Department of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
6
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
7
Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, 1090, Vienna, Austria.
8
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna and Medical University of Vienna, Austria.
9
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, UK.
10
Unit of Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, Austria.

Abstract

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:

ALCL; ALK kinase; IL-10; IL-21; IL-22; cytokines; miR-155

PMID:
25820993
PMCID:
PMC4557053
DOI:
10.1002/path.4539
[Indexed for MEDLINE]
Free PMC Article

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