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

Ji Hoon Phi, Choong-Hyun Sun, Se-Hoon Lee, Seungmook Lee, Inho Park, Seung Ah Choi, Sung-Hye Park, Ji Yeoun Lee, Kyu-Chang Wang, Seung-Ki Kim, Chul-Kee Park, Hong Seok Yun

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)848
JournalBMC Cancer
Volume19
Issue number1
DOIs
StatePublished - 28 Aug 2019

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Genes
Exome
Therapeutics
Tumor Cell Line
RNA Sequence Analysis
Typical Teratoid Rhabdoid Tumor
Atypical Teratoid Tumor
Comparative Genomic Hybridization
G1 Phase
Gene Silencing
Cell Cycle Checkpoints
Transcriptome
Brain Neoplasms
Single Nucleotide Polymorphism
Cell Cycle
Down-Regulation
Genome
RNA
Neoplasms
nucleophosmin

Cite this

@article{29a6ac6b43cf45c68a2b4e379a340a77,
title = "NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors",
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.",
author = "Phi, {Ji Hoon} and Choong-Hyun Sun and Se-Hoon Lee and Seungmook Lee and Inho Park and Choi, {Seung Ah} and Sung-Hye Park and Lee, {Ji Yeoun} and Kyu-Chang Wang and Seung-Ki Kim and Chul-Kee Park and Yun, {Hong Seok}",
year = "2019",
month = "8",
day = "28",
doi = "10.1186/s12885-019-6044-z",
language = "English",
volume = "19",
pages = "848",
journal = "BMC cancer",
issn = "1471-2407",
publisher = "BioMed Central Ltd.",
number = "1",

}

NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors. / Phi, Ji Hoon; Sun, Choong-Hyun; Lee, Se-Hoon; Lee, Seungmook; Park, Inho; Choi, Seung Ah; Park, Sung-Hye; Lee, Ji Yeoun; Wang, Kyu-Chang; Kim, Seung-Ki; Park, Chul-Kee; Yun, Hong Seok.

In: BMC Cancer, Vol. 19, No. 1, 28.08.2019, p. 848.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors

AU - Phi, Ji Hoon

AU - Sun, Choong-Hyun

AU - Lee, Se-Hoon

AU - Lee, Seungmook

AU - Park, Inho

AU - Choi, Seung Ah

AU - Park, Sung-Hye

AU - Lee, Ji Yeoun

AU - Wang, Kyu-Chang

AU - Kim, Seung-Ki

AU - Park, Chul-Kee

AU - Yun, Hong Seok

PY - 2019/8/28

Y1 - 2019/8/28

N2 - 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.

AB - 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.

U2 - 10.1186/s12885-019-6044-z

DO - 10.1186/s12885-019-6044-z

M3 - Article

VL - 19

SP - 848

JO - BMC cancer

JF - BMC cancer

SN - 1471-2407

IS - 1

ER -