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/EBPß and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPß 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/EBPß 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).
Subject(s)
Chromosomes, Human, Pair 2 , Chromosomes, Human, Pair 5 , Lymphoma, Large-Cell, Anaplastic/genetics , MicroRNAs/genetics , Translocation, Genetic , Anaplastic Lymphoma Kinase , 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 , DNA Methylation , Gene Expression Regulation, Neoplastic , Genetic Therapy/methods , Humans , Lymphoma, Large-Cell, Anaplastic/metabolism , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, Large-Cell, Anaplastic/therapy , Mice, Inbred NOD , Mice, SCID , MicroRNAs/metabolism , Promoter Regions, Genetic , Receptor Protein-Tyrosine Kinases/deficiency , Receptor Protein-Tyrosine Kinases/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , Suppressor of Cytokine Signaling 1 Protein , Suppressor of Cytokine Signaling Proteins/genetics , Suppressor of Cytokine Signaling Proteins/metabolism , Transfection , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: Peripheral T-cell lymphomas (PTCLs) and natural killer (NK) or T-cell non-Hodgkin's lymphomas (NHLs) are a rare and heterogeneous class of diseases with generally poor prognosis. This work intends to provide a focused primer on clinical diagnosis, current treatment regimens, and novel therapeutic approaches. The recent WHO classification has defined 18 different subtypes of PTCL and NK T-cell lymphomas. Diagnosis is mainly based on histology, flow-cytometric analysis of surface molecules in the blood and bone marrow, cytogenetics/fluorescence in situ hybridization (FISH), and T-cell receptor (TCR) rearrangement. Staging as well as follow-up diagnostic procedures rely on imaging techniques such as computerized tomography (CT) and positron emission tomography (PET). Current chemotherapeutic regimens such as CHOP result in a 60 - 70% response rate; however, 5-year survival is only around 30%. Therefore, new treatment strategies are urgently needed. Currently, different drug classes are under scrutiny. AREAS COVERED: The authors discuss substances that directly target the tumor cells. The article includes such substances as antimetabolites, antibodies, histone deacetylase inhibitors, tyrosine kinase inhibitors, and immunomodulatory substances such as lenalidomide. EXPERT OPINION: In the future a close collaboration of geneticists, biochemists, and clinicians together with new technologies such as deep sequencing will allow the refinement of treatment strategies in many diseases including PTCLs and NHLs. This refinement will allow treatments to be prepared according to the need of the individual patient.
