Abstract 3005: Significant roles of aberrant miRNA expressions in NK-cell lymphomagenesis
Authors: Tagawa Hiroyuki , Yamanaka Yasuo , Watanabe Atsushi , Sawada Kenichi 
Published: February 2011

Background: Natural Killer (NK) cell lymphomas/leukemias are characterized groups of highly aggressive lymphoid malignancies, which are comprised of “extranodal NK/T cell lymphoma, nasal type” and “aggressive NK-cell leukemia”. Notably, these two subtypes show many similarities in their morphologic features, immmunophenotypes and genotypes, and are invariably associated with Epstein-Barr virus (EBV), which suggests they may share the same genetic alterations. The gene(s) responsible for natural killer (NK)-cell lymphoma/leukemia have not been identified.

Materials and Methods: In the present study, we used miRNA array, Northern and quantitative PCR analyses to screen for and quantitatively assess miRNA expression in NK-cell lymphomas/leukemias using 70 probe sets of miRNAs. For function analysis, we conducted antisense oligonucleotides and lentivirus transfection assays using NK-cell lymphoma cell lines.

Results: 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 significantly higher than those seen in normal natural killer (CD3-CD56+) cells (n=8). Furthermore, miR-150 expression of primary samples and cell lines was significantly lower than CD3-CD56+ normal cells. To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides targeting miR-21 (ASO-21) and/or miR-155 (ASO-155) in NK-cell lymphoma lines overexpressing one or both of these miRNAs. Conversely, cells showing little endogenous expression of miR-21, miR-155 and miR-150 were transduced using lentiviral vectors, leading to their overexpression. Reducing expression of miR-21 or miR-155 led to upregulation of phosphatase and tensin homologue (PTEN), programmed cell death 4 (PDCD4), or Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1). ASO-21- and ASO-155-treated cell lines all showed downregulation of phosphorylated AKTser473 (pAKT). Moreover, transduction with either miR-21 or miR-155 led to downregulation of PTEN and PDCD4, or SHIP1 with upregulation of pAKT. Because apoptosis and cell cycle arrest were induced by transduction of miR-150 into NK-cell lymphoma cell lines, the miRNA is possible candidate of tumor suppressive miRNA in this tumor entity. Detection for direct target of the miR-150 is now underway.

Conclusions: Because recent reports suggest that EBV infection can lead directly to upregulation of miR-21 and miR-155, aberrant overexpressions of these miRNAs via EBV infection could be the first-hit genetic alterations during NK-cell lymphomagenesis. Collectively, these results provide important new insight into the pathogenesis of NK-cell lymphoma/leukemia and suggest targeting these miRNAs may represent a useful approach to treating NK-cell lymphoma/leukemia.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3005.