Oncogenic role of miR155 in anaplastic large cell lymphoma lacking the t(2;5) translocation

Abstract

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, nonHodgkin'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 nucleophosminanaplastic lymphoma tyrosine kinase (NPMALK) fusion protein (ALCL ALK+). However, little is known about the molecular features and tumour drivers in ALKnegative ALCL (ALCL ALK), which is characterized by a worse prognosis. We found that ALCL ALK, in contrast to ALCL ALK+, lymphomas display high miR155 expression. Consistent with this, we observed an inverse correlation between miR155 promoter methylation and miR155 expression in ALCL. However, no direct effect of the ALK kinase on miR155 levels was observed. Ago2 immunoprecipitation revealed miR155 as the most abundant miRNA, and enrichment of target mRNAs C/EBP and SOCS1. To investigate its function, we overexpressed miR155 in ALCL ALK+ cell lines and demonstrated reduced levels of C/EBP and SOCS1. In murine engraftment models of ALCL ALK, we showed that antimiR155 mimics are able to reduce tumour growth. This goes handinhand with increased levels of cleaved caspase3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR155 induces IL22 expression and suppresses the C/EBP target IL8. These data suggest that miR155 can act as a tumour driver in ALCL ALK and blocking miR155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.(VLID)484329