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). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin’s T cell lymphoma (NHL) that occurs mostly in children and in adults
Employing an independent cohort of ALCL patient tumours, we show that miR-155 expression is significantly higher in anaplastic lymphoma kinase receptor tyrosine kinase (ALK)− (n = 11) as compared to ALCL
These data are in keeping with the primary patient tumour data, whereby miR-155 expression is more prevalent in ALCL ALK− cases
Summary
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin’s T cell lymphoma (NHL) that occurs mostly in children and in adults. The majority of patients bear the typical t(2;5) aberration, which leads to fusion of the N-terminal oligomerization domain of nucleophosmin (NPM) to the cytoplasmic portion of the anaplastic lymphoma kinase receptor tyrosine kinase (ALK) [1,2]. This results in dimerization and constitutive activation of the kinase and its downstream effectors, including PI3K–AKT [3], JAK3–STAT3 [4,5], MAPK–ERK [6,7,8], PDGFRB [9] and PLC–PKC [10]. The WHO classification published in 2008 provisionally defines ALCL with and without the ALK translocation as two different disease entities, mainly based on the diverging clinical course [23]
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