Abstract 1108: Subtype specific expression of immnune-modulating miR-155 and miR-146a in anaplastic large cell lymphoma

Abstract

Abstract Anaplastic large-cell lymphoma (ALCL) is a mature T-cell malignancy that is subdivided further into two distinct disease entities based on the presence or absence of the anaplastic lymphoma kinase (ALK) fusion protein. ALK+ ALCL bears the t(2;5) (p23;q35) translocation in greater than 80% of cases, which results in the expression of the chimeric nucleophosmin (NPM)-ALK. This leads to the activation of many different growth-promoting and anti-apoptotic pathways, including PI3K/Akt1/mTOR, Jak/Stat and AP-1. Recently, micro-RNAs (miRNAs) have emerged as tiny but potent molecules to regulate cell differentiation and proliferation. In a recent publication we have reported that miR-155 is up-regulated in ALK+ and down-regulated in ALK- ALCL. We have now identified an additional miRNA, miR-146a, that is significantly higher expressed in ALK- ALCL. Both miRNAs are strongly induced by T-cell activation. We report here that in ALCL cell lines that highly express miR-155 (like ALK- Mac1 and Mac2a) its target protein CCAAT-enhancer-binding protein ≤ (C/EBPβ) is suppressed and moreover reintroduction of miR-155 in cell lines that have low miR-155 levels (Karpas-299, SR786, SU-DHL-1, SUP-M2) can actively down-regulate C/EBPβ. Conversely, high expression of miR-146a in primary ALK- ALCL FFPE specimens corresponds to low expression of its target protein IL1 receptor-associated kinase 1 in ALK - cell lines. Due to the known roles of miR-155 and miR-146a we assessed cytokine release in a set of ALCL cell lines with and without the ALK translocation. Interestingly, we found expression of cytokines including IL-6, IL-10, IL-21 and IL-22 in ALCL cell lines. Inflammatory cytokines IL-6, IL-21 and IL-22 were 4 to 10-fold higher in ALK- cell lines, whereas anti-inflammatory IL-10 levels were not related to ALK status. Reintroduction of miR-155 into the ALK+ cell lines Karpas-299 and SR786 was able to enhance expression of IL-22. To test the influence of miR-155 on ALK- ALCL tumor growth in vivo we injected 5x10^6 Mac1 cells with low (transfected with anti-miR) or high miR-155 (transfected with pre-miR) into the flanks of BALB/c mice. High miR-155 led to a significantly enhanced tumor growth and increased IL-22 in the serum, suggesting miR-155 as tumor driver and potential therapeutic target in ALK- ALCL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1108. doi:1538-7445.AM2012-1108