The gene(s) responsible for natural killer (NK)-cell lymphoma/leukemia have not been identified. In the present study, we found that in NK-cell lymphoma lines (n ؍ 10) and specimens of primary lymphoma (n ؍ 10), levels of miR-21 and miR-155 expression were inversely related and were significantly greater than those found in normal natural killer (CD3 ؊ CD56 ؉ ) cells (n ؍ 8). To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) tar-
IntroductionNatural killer (NK)-cell lymphomas/leukemias are characterized groups of highly aggressive lymphoid malignancies, which are composed of "extranodal NK/T-cell lymphoma, nasal type" and "aggressive NK-cell leukemia." 1 Notably, these 2 subtypes show many similarities in their morphologic features, immunophenotypes, and genotypes and are invariably associated with EpsteinBarr virus (EBV), which suggests they may share the same genetic alterations. To assign a classification, the World Health Organization classification uses cytogenetic and molecular features to characterize lymphoma subtypes. 1 For example, it is known that various genomic translocations and genetic alterations, including BCL2, CCDN1, and c-MYC, occur in B-cell lymphomas. These disease-specific genetic translocations characterize lymphoma subtypes, such as follicular lymphoma characterized by BCL2 rearrangement, mantle-cell lymphoma characterized by CCDN1 rearrangement, and Burkitt lymphoma characterized by c-MYC rearrangement. However, although the World Health Organization classification recognizes NK-cell lymphomas/leukemias as distinct clinicopathologic entities, disease-specific translocations and the gene(s) affected in the 2 subtypes have not yet been identified. It was previously reported that a 6q deletion occurs in approximately 10% to 20% of NK-cell lymphomas/leukemias 2-7 ; however, this loss may not be disease specific because it has been observed in a variety of cancers, including solid tumors and hematologic malignancies. It is currently unclear whether the loss is a primary or progression-associated event.It was recently discovered that some microRNAs (miRNAs) are oncogenic in B-cell lymphomas. For example, aberrant overexpression of 2 miRNAs, miR-17-92 and miR-155, is closely associated with B-cell lymphomagenesis. 8 With respect to miR-17-92, we recently demonstrated that the polycistron can down-regulate CDKN1A/p21 in B-cell lymphomagenesis and promote cell-cycle regulation. 8 Furthermore, it is unlikely that aberrant expression of miRNAs is restricted to B-cell lymphomas, and it may occur in other lymphoma subtypes, including T/NK-cell lymphomas. In the present study, therefore, we used Northern and quantitative polymerase chain reaction (PCR) analyses to screen for and quantitatively assess miRNA expression in NK-cell lymphomas/leukemias and found that miR-21 and miR-155 were overexpressed in NK-cell lymphoma/leukemia. Moreover, the effects of antisense oligonucleotides (ASOs) revealed that miR-21 and miR-15...