Abstract
Anaplastic large cell lymphoma (ALCL) is divided into two systemic diseases according to the expression of the anaplastic lymphoma kinase (ALK). We investigated the differential expression of miRNAs between ALK+ ALCL, ALK- ALCL cells and normal T-cells using next generation sequencing (NGS). In addition, a C/EBPβ-dependent miRNA profile was generated. The data were validated in primary ALCL cases. NGS identified 106 miRNAs significantly differentially expressed between ALK+ and ALK- ALCL and 228 between ALK+ ALCL and normal T-cells. We identified a signature of 56 miRNAs distinguishing ALK+ ALCL, ALK- ALCL and T-cells. The top candidates significant differentially expressed between ALK+ and ALK- ALCL included 5 upregulated miRNAs: miR-340, miR-203, miR-135b, miR-182, miR-183; and 7 downregulated: miR-196b, miR-155, miR-146a, miR-424, miR-503, miR-424*, miR-542-3p. The miR-17-92 cluster was also upregulated in ALK+ cells. Additionally, we identified a signature of 3 miRNAs significantly regulated by the transcription factor C/EBPβ, which is specifically overexpressed in ALK+ ALCL, including the miR-181 family. Of interest, miR-181a, which regulates T-cell differentiation and modulates TCR signalling strength, was significantly downregulated in ALK+ ALCL cases. In summary, our data reveal a miRNA signature linking ALK+ ALCL to a deregulated immune response and may reflect the abnormal TCR antigen expression known in ALK+ ALCL.
Highlights
Anaplastic large cell lymphoma (ALCL) represents a distinct group of T-cell non-Hodgkin lymphomas, which are separated according to the World Health Organization (WHO) classification [1] into two different disease entities based on the presence or absence of a chromosomal translocation involving the anaplastic lymphoma kinase (ALK) gene
We previously reported that in ALK+ ALCL, ALK protein induces the expression of the transcription factor C/EBPβ primarily through STAT3, and that C/EBPβ plays a central role in ALK-mediated oncogenesis [29,31]
In order to identify the miRNAs expressed in ALK+ ALCL, and possibly regulated by C/EBPβ, we performed miRNA next generation sequencing (NGS) of ALK+ and ALK- cell lines, normal T cells and ALK+ ALCL cell lines after C/EBPβ silencing
Summary
Anaplastic large cell lymphoma (ALCL) represents a distinct group of T-cell non-Hodgkin lymphomas, which are separated according to the World Health Organization (WHO) classification [1] into two different disease entities based on the presence or absence of a chromosomal translocation involving the anaplastic lymphoma kinase (ALK) gene. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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