In the current study, in order to identify the miRNAs specifically expressed in ALK+ ALCL, and possibly regulated by C/EBP��, we performed miRNA NGS of ALK+ and ALK- cell lines, normal T cells and ALK+ ALCL cell lines after C/EBP�� silencing. PCA analysis of the sequencing data confirmed characteristic patterns among samples of different entities and with downregulated C/EBP�� expression, confirming the use of this approach to characterize the miRNA expression pattern in ALCL. We show that the miRNA signature of ALK- ALCL has a different GSI-IX profile compared with normal T cells, and to partially overlap with the miRNA expression prolife of ALK+ ALCL, indicating that the two ALCL subgroups are closely related. Comparison of our data with two previously published miRNA profiles of ALK+ ALCL provided further validation of our results. Not surprisingly, using NGS we found more significantly differentially expressed miRNAs between the different entities than it was feasible using miRNA arrays or a high throughput TaqMan quantitative real-time PCR approach. Although there are considerable differences mainly due to the technical approach and material used, our miRNA signature shows overlapping results with 26 miRNAs identified by Merkel et al. and Liu et al.. Of these, nine miRNAs were found regulated or preferentially associated with ALK+ ALCL in all three studies. The overlapping detection of deregulated miRNAs in the different studies indicates that at least some of them most probably contribute to ALK mediated oncogenesis and/or tumor biology. The low expression of miR-146a and miR-155, both on the top of the list of differentially expressed miRNAs in our study, as a constant feature in ALK+ ALCL, is intriguing because evidence suggests that these two miRNAs may have crucial roles in regulating the innate immune response and that the putative targets of both miRNAs are components of the toll-like receptor signaling machinery. miR-146a is a member of the miR-146 miRNA family consisting of two evolutionary conserved miRNA genes; miR-146a and miR-146b. They share the same seed sequence but are encoded by different loci in the genome. miR-146a expression occurs in an NF-��B dependent manner in response to LPS. Recent studies have suggested that miR-146a acts as a negative feedback regulator of the innate immune response by targeting two adapter proteins TNF-receptor-associated factor 6 and IL-1 receptor-associated kinase 1 that are crucial for proinflammatory signaling and activation of NF- ��B. In contrast, lack of miR-146a expression results in exaggerated inflammatory response and spontaneous autoimmune disorders. Aging miR-146a deficient mice developed myeloid sarcomas and lymphomas associated with chronic NF-��B activation, which suggests that miR-146a may also function as a tumor suppressor gene. The excessive inflammation seen in these mice argues in favor of a connection between chronic inflammation and cancer. Most BIBW2992 interesting is the fact that miR-146a expression might be involved in cell fate determination in T cells because its expression is associated with T cell expansion and a T-helper 1 phenotype with strong TCR stimulation, and low expression induces a Th2 differentiation. Furthermore, miR-155 deficient mice, in addition to having a defect in the germinal center reaction, show a skewing of their T cells toward Th2 differentiation with low production of interferon ��. Accordingly, our analysis of the cytokine expression in cell lines demonstrated that ALK+ ALCL cells are characterized by very high expression of IL-10 with very low expression of interferon ��.