Abstract 2170: Genomic profiling and pathway significances of natural killer cell lymphoma (NKL): Implication for NK lymphomagenesis and genomic targeting therapeutics

Abstract

Abstract Natural killer cell lymphoma (NKL) is a highly aggressive form of lymphoid malignancy (Suzuki et al. BLOOD 2009). We hypothesized that the comparison of differentially expressed genes of NKL vs normal NK cells would be a rational approach for enhancing our understanding of NK lymphomagenesis and lead to the discovery of genomic markers and potential therapeutic targets. Isolated RNA from highly enriched peripheral blood NK cells (CD3-, CD56+; PBNK) and human IL2-independent NKL cell line (NK-92MI) were subjected to microarray studies using Affymetrix U133A_2. Gene data were subjected to Agilent GeneSpring analyses. Welch test were used to perform statistical analysis and fold change of < 2.0 and values of p<0.05 were considered to be significant. NK-92MI NKL vs PBNK expressed high CD3ε (3.4F UP), presumably due to the constitutive expression of IL-2 in NK-92MI. The gene array studies identified 1284 genes that were upregulated (>2F) and 1558 genes that were downregulated (>2F) in NKL vs PB NKs. The pathway mapping studies identified 22 pathways (p<0.05), including cytokine-cytokine receptor interaction (CCRI) (12 genes), pathways in cancer (PIC) (26 genes) and p53 signaling (13 genes), involved in up-regulation, whereas 26 pathways (p<0.05), including antigen processing and presentation (APP) (12 genes), CCRI pathway (29 genes), and MAPK signaling (36 genes), involved in down-regulation. Altered genes in CCRI pathway included CCL18 (1257F UP), CXCL2 (583F DOWN), IL7R (379F DOWN), TNFRSF25 (276F DOWN), IL1B (198F DOWN), CX3CR1 (181F DOWN). Altered genes in MAPK pathway included DUSP4 (330F DOWN), IL1B (198F DOWN), CD14 (120F DOWN), CACNA2D2 (51F DOWN). Altered genes in p53 pathway included IGF1 (465F UP), RRM2 (144F UP), CDKN2A (56F UP). Altered genes in PIC pathway included BIRC5 (117F UP), FN1 (73F UP), RALBP1 (158F DOWN), TCF7L2 (137F DOWN), CTBP2 (122F DOWN), PTK2 (107F DOWN). NK cell mediated cytotoxicity pathway was not significantly changed (p <0.2). However, 16 and 9 genes were demonstrated to be up and down regulated, including NCR2 (211F UP), NFATC1 (100F DOWN), DAP-12/TYROBP (64F DOWN), and IFNGR2 (40F DOWN). CCL18 chemokine is a known non-invasive biomarker in many diseases. Granzyme protein, which activates caspase-3 (CASP3), was down-regulated in NKL. BIRC5 (survivin) gene, which inhibits CASP3, was increased in NKL. CASP3 and BIRC5 counteract a default induction of apoptosis in G2/M phase. NCR2 and DAP-12 specifically regulate NK mediated cytotoxicity. These data suggest that CCRI, p53, APP, and MAPK signaling pathways may be involved in NK lymphomagenesis. The 108 altered genes in these pathways may serve in part to characterize the genetic signature in NKL. Furthermore, CCL18, NCR2, BIRC5, and DAP-12 together may serve as genomic markers to identify NKL and may be candidate targets for novel therapeutics. 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 2170.