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NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors

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Authors
Phi, Ji Hoon; Sun, Choong-Hyun; Lee, Se-Hoon; Lee, Seungmook; Park, Inho; Choi, Seung A; Park, Sung-Hye; Lee, Ji Yeoun; Wang, Kyu-Chang; Kim, Seung-Ki; Yun, Hongseok; Park, Chul-Kee
Issue Date
2019-08-28
Publisher
BioMed Central
Citation
BMC Cancer, 19(1):848
Keywords
Atypical teratoid/rhabdoid tumorNPM1Nucleophosmin
Abstract
Background
Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets.

Methods
Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines.

Results
WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells.

Conclusions
We propose that NPM1 is a novel therapeutic target for AT/RTs.
ISSN
1471-2407
Language
English
URI
http://hdl.handle.net/10371/162626
DOI
https://doi.org/10.1186/s12885-019-6044-z
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College of Medicine/School of Medicine (의과대학/대학원)Pediatrics (소아과학전공)Journal Papers (저널논문_소아과학전공)
College of Medicine/School of Medicine (의과대학/대학원)Neurosurgery (신경외과학전공)Journal Papers (저널논문_신경외과학전공)
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