Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Zhaoming Li; Xudong Zhang; Weili Xue; Yanjie Zhang; Chaoping Li; Yue Song; Mei Mei; Lisha Lu; Yingjun Wang; Zhiyuan Zhou; Mengyuan Jin; Yangyang Bian; Lei Zhang; Xinhua Wang; Ling Li; Xin Li; Xiaorui Fu; Zhenchang Sun; Jingjing Wu; Feifei Nan; Yu Chang; Jiaqin Yan; Hui Yu; Xiaoyan Feng; Guannan Wang; Dandan Zhang; Xuefei Fu; Yuan Zhang; Ken H. Young; Wencai Li; Mingzhi Zhang

doi:10.1038/s41467-019-12032-9

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Zhaoming Li, Xudong Zhang, Weili Xue, Yanjie Zhang, Chaoping Li, Yue Song, Mei Mei, Lisha Lu, Yingjun Wang, Zhiyuan Zhou, Mengyuan Jin, Yangyang Bian, Lei Zhang, Xinhua Wang, Ling Li, Xin Li, Xiaorui Fu, Zhenchang Sun, Jingjing Wu, Feifei NanYu Chang, Jiaqin Yan, Hui Yu, Xiaoyan Feng, Guannan Wang, Dandan Zhang, Xuefei Fu, Yuan Zhang, Ken H. Young, Wencai Li, Mingzhi Zhang

Hematopathology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaq^fl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.

Original language	English (US)
Article number	4209
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12032-9
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Li, Z, Zhang, X, Xue, W, Zhang, Y, Li, C, Song, Y, Mei, M, Lu, L, Wang, Y, Zhou, Z, Jin, M, Bian, Y, Zhang, L, Wang, X, Li, L, Li, X, Fu, X, Sun, Z, Wu, J, Nan, F, Chang, Y, Yan, J, Yu, H, Feng, X, Wang, G, Zhang, D, Fu, X, Zhang, Y, Young, KH, Li, W & Zhang, M 2019, 'Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma', Nature communications, vol. 10, no. 1, 4209. https://doi.org/10.1038/s41467-019-12032-9

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title = "Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma",

abstract = "Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.",

author = "Zhaoming Li and Xudong Zhang and Weili Xue and Yanjie Zhang and Chaoping Li and Yue Song and Mei Mei and Lisha Lu and Yingjun Wang and Zhiyuan Zhou and Mengyuan Jin and Yangyang Bian and Lei Zhang and Xinhua Wang and Ling Li and Xin Li and Xiaorui Fu and Zhenchang Sun and Jingjing Wu and Feifei Nan and Yu Chang and Jiaqin Yan and Hui Yu and Xiaoyan Feng and Guannan Wang and Dandan Zhang and Xuefei Fu and Yuan Zhang and Young, {Ken H.} and Wencai Li and Mingzhi Zhang",

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year = "2019",

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doi = "10.1038/s41467-019-12032-9",

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T1 - Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

AU - Li, Zhaoming

AU - Zhang, Xudong

AU - Xue, Weili

AU - Zhang, Yanjie

AU - Li, Chaoping

AU - Song, Yue

AU - Mei, Mei

AU - Lu, Lisha

AU - Wang, Yingjun

AU - Zhou, Zhiyuan

AU - Jin, Mengyuan

AU - Bian, Yangyang

AU - Zhang, Lei

AU - Wang, Xinhua

AU - Li, Ling

AU - Li, Xin

AU - Fu, Xiaorui

AU - Sun, Zhenchang

AU - Wu, Jingjing

AU - Nan, Feifei

AU - Chang, Yu

AU - Yan, Jiaqin

AU - Yu, Hui

AU - Feng, Xiaoyan

AU - Wang, Guannan

AU - Zhang, Dandan

AU - Fu, Xuefei

AU - Zhang, Yuan

AU - Young, Ken H.

AU - Li, Wencai

AU - Zhang, Mingzhi

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.

AB - Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.

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JO - Nature communications

JF - Nature communications

IS - 1

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ER -

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

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