Oncotarget

Research Papers:

Gene expression profiling of hematologic malignant cell lines resistant to oncolytic virus treatment

Nam Hee Lee, Mikyung Kim, Sung Yong Oh, Seong-Geun Kim, Hyuk-Chan Kwon, Tae-Ho Hwang _

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Oncotarget. 2017; 8:1213-1225. https://doi.org/10.18632/oncotarget.13598

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Abstract

Nam Hee Lee1,2, Mikyung Kim1, Sung Yong Oh3, Seong-Geun Kim4, Hyuk-Chan Kwon1, Tae-Ho Hwang5,6

1SillaJen, Inc., Busan, Korea

2Department of Physiology, Pusan National University, School of Medicine, Yangsan, Korea

3Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea

4Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea

5Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Korea

6Gene and Cell Therapy Research Center for Vessel-associated Diseases, School of Medicine, Pusan National University, Yangsan, Korea

Correspondence to:

Tae-Ho Hwang, email: thhwang@pusan.ac.kr

Hyuk-Chan Kwon, email: hckwon@sillajen.com

Keywords: oncolytic virus, gene expression profiling, hematologic malignancy

Received: August 20, 2016    Accepted: November 04, 2016    Published: November 25, 2016

ABSTRACT

Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.


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