Abstract
Abstract Introduction: ARS-interacting multifunctional protein 2 (AIMP2) has been known to play an important role in the regulation of cell fate, and acts as a tumor-suppressive agent. Unlike normal AIMP2, AIMP2-DX2, a splicing variant of exon 2 deletion, promotes carcinogenic stress. We recently discovered that AIMP2-DX2 is an important poor prognostic factor in acute myeloid leukemia. Likewise, we conjectured AIMP2-DX2 would have a potential role in lymphoid hematologic malignancy. The aim of this study is to investigate the biologic role of AIMP2-DX2 in lymphoma. Materials and Methods: We studied the composition of genetically categorized variation in lymphoma using 38 diffuse large B cell lymphomas (DLBC) and 56 germinal center B cell lymphoma (MALY) of RNA sequencing data shared by International Cancer Genome Consortium (ICGC). The Differentially Expressed Gene (DEG) analysis method was applied to the RNA data aligned to the human reference, and the different expression pattern in each group was confirmed by nonbiased clustering. We observed whether clustering identifies certain subset of high AIMP2-DX2 level tumors. The Gene Set Enrichment Analysis (GSEA) was performed to confirm the statistical differences or similarities in the number of genes in each subgroup with adjusted p-value <0.05 to identify the representative pathway. Malignant lymphoma-based NAMALWA and HS-sultan cell lines were used and expression level of DX2 was quantitatively analyzed by quantitative real-time PCR. The relationship between AIMP2-DX2 and oncogenic signaling pathway components was verified with Western blotting. Results: As a result of DEG using unbiased clustering, we could successfully cluster patients into two groups in both DLBC and MALY. Interestingly, unbiased clustering of tumors resulted in a distinct cluster composed of AIMP2-DX2 high-expressing tumors. This phenomenon was observed both in DLBCL and MALY. GSEA analysis revealed that, in DLBC, the expression of JAK-STAT, MAPK, KRAS, and MYC-related genes was increased while the expression of the spliceosome-related genes was reduced as DX2 expression increased. MALY also showed high expression of JAK-STAT, MAPK and KRAS-associated genes and high expression of WNT signaling pathway in high AIMP2-DX2 samples. Using cell lines, we confirmed the expression of AKT MEK, and ERK correlates in malignant lymphoma cell line with expression of AIMP2-DX2 than in cell line with low AIMP2-DX2 expression. Conclusion: Thus, our data suggest that differences in expression of DX2 cause lymphomagenesis by affecting other oncogenic signaling pathway, such as JAK-STAT, MAPK and KRAS signaling pathways are related to AIMP2 DX2-induced lymphoid hematologic malignancy. Citation Format: Yungyeong Park, Heejoo Han, Seulki Song, Dongchan Kim, Youngil Koh, Sung-Soo Yoon. The correlation of AIMP2-DX2 expression and oncogenic signaling pathways in lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5517.
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