Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)

Abstract USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of > 2...

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Autores principales:	Timothy I. Shaw, Li Dong, Liqing Tian, Chenxi Qian, Yu Liu, Bensheng Ju, Anthony High, Kanisha Kavdia, Vishwajeeth R. Pagala, Bridget Shaner, Deqing Pei, John Easton, Laura J. Janke, Shaina N. Porter, Xiaotu Ma, Cheng Cheng, Shondra M. Pruett-Miller, John Choi, Jiyang Yu, Junmin Peng, Wei Gu, A. Thomas Look, James R. Downing, Jinghui Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cb7c285f227c42abb04cd250bb2d752a
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spelling	oai:doaj.org-article:cb7c285f227c42abb04cd250bb2d752a2021-12-02T13:34:50ZIntegrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)10.1038/s41598-021-84647-22045-2322https://doaj.org/article/cb7c285f227c42abb04cd250bb2d752a2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84647-2https://doaj.org/toc/2045-2322Abstract USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of > 200 T-ALL transcriptomes linked USP7 haploinsufficiency with decreased activities of E-proteins. E-proteins are also negatively regulated by TAL1, leading to concerted down-regulation of E-protein target genes involved in T-cell development. In T-ALL cell lines, we showed the physical interaction of USP7 with E-proteins and TAL1 by mass spectrometry and ChIP-seq. Haploinsufficient but not complete CRISPR knock-out of USP7 showed accelerated cell growth and validated transcriptional down-regulation of E-protein targets. Our study unveiled the synergistic effect of USP7 haploinsufficiency with aberrant TAL1 activation on T-ALL, implicating USP7 as a haploinsufficient tumor suppressor in T-ALL. Our findings caution against a universal oncogene designation for USP7 while emphasizing the dosage-dependent consequences of USP7 inhibitors currently under development as potential cancer therapeutics.Timothy I. ShawLi DongLiqing TianChenxi QianYu LiuBensheng JuAnthony HighKanisha KavdiaVishwajeeth R. PagalaBridget ShanerDeqing PeiJohn EastonLaura J. JankeShaina N. PorterXiaotu MaCheng ChengShondra M. Pruett-MillerJohn ChoiJiyang YuJunmin PengWei GuA. Thomas LookJames R. DowningJinghui ZhangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Timothy I. Shaw Li Dong Liqing Tian Chenxi Qian Yu Liu Bensheng Ju Anthony High Kanisha Kavdia Vishwajeeth R. Pagala Bridget Shaner Deqing Pei John Easton Laura J. Janke Shaina N. Porter Xiaotu Ma Cheng Cheng Shondra M. Pruett-Miller John Choi Jiyang Yu Junmin Peng Wei Gu A. Thomas Look James R. Downing Jinghui Zhang Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)
description	Abstract USP7, which encodes a deubiquitylating enzyme, is among the most frequently mutated genes in pediatric T-ALL, with somatic heterozygous loss-of-function mutations (haploinsufficiency) predominantly affecting the subgroup that has aberrant TAL1 oncogene activation. Network analysis of > 200 T-ALL transcriptomes linked USP7 haploinsufficiency with decreased activities of E-proteins. E-proteins are also negatively regulated by TAL1, leading to concerted down-regulation of E-protein target genes involved in T-cell development. In T-ALL cell lines, we showed the physical interaction of USP7 with E-proteins and TAL1 by mass spectrometry and ChIP-seq. Haploinsufficient but not complete CRISPR knock-out of USP7 showed accelerated cell growth and validated transcriptional down-regulation of E-protein targets. Our study unveiled the synergistic effect of USP7 haploinsufficiency with aberrant TAL1 activation on T-ALL, implicating USP7 as a haploinsufficient tumor suppressor in T-ALL. Our findings caution against a universal oncogene designation for USP7 while emphasizing the dosage-dependent consequences of USP7 inhibitors currently under development as potential cancer therapeutics.
format	article
author	Timothy I. Shaw Li Dong Liqing Tian Chenxi Qian Yu Liu Bensheng Ju Anthony High Kanisha Kavdia Vishwajeeth R. Pagala Bridget Shaner Deqing Pei John Easton Laura J. Janke Shaina N. Porter Xiaotu Ma Cheng Cheng Shondra M. Pruett-Miller John Choi Jiyang Yu Junmin Peng Wei Gu A. Thomas Look James R. Downing Jinghui Zhang
author_facet	Timothy I. Shaw Li Dong Liqing Tian Chenxi Qian Yu Liu Bensheng Ju Anthony High Kanisha Kavdia Vishwajeeth R. Pagala Bridget Shaner Deqing Pei John Easton Laura J. Janke Shaina N. Porter Xiaotu Ma Cheng Cheng Shondra M. Pruett-Miller John Choi Jiyang Yu Junmin Peng Wei Gu A. Thomas Look James R. Downing Jinghui Zhang
author_sort	Timothy I. Shaw
title	Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)
title_short	Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)
title_full	Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)
title_fullStr	Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)
title_full_unstemmed	Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)
title_sort	integrative network analysis reveals usp7 haploinsufficiency inhibits e-protein activity in pediatric t-lineage acute lymphoblastic leukemia (t-all)
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cb7c285f227c42abb04cd250bb2d752a
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Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)

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