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Blood. 2018 Apr 26;131(17):1931-1941. doi: 10.1182/blood-2017-07-797209. Epub 2018 Feb 23.

Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments.

Author information

1
Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Korea.
2
The Jackson Laboratory for Genomic Medicine, Farmington, CT.
3
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
4
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
5
Department of Life Science, Ewha Womans University, Seoul, Korea.
6
Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea.
7
Department of Pathology, Ewha Womans University College of Medicine, Seoul, Korea.
8
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
9
Department of Pathology, Ajou University School of Medicine, Suwon, Korea.
10
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
11
Department of Surgery and.
12
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
13
The Jackson Laboratory, Sacramento, CA.
14
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
15
Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea; and.
16
Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea.

Abstract

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV+-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+-DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumor growth in EBV+-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.

PMID:
29475961
PMCID:
PMC5921963
DOI:
10.1182/blood-2017-07-797209
[Indexed for MEDLINE]
Free PMC Article

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