Academic Journal
Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL)
| Title: | Integrative network analysis reveals USP7 haploinsufficiency inhibits E-protein activity in pediatric T-lineage acute lymphoblastic leukemia (T-ALL) |
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| Authors: | 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 |
| Source: | Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021) |
| Publisher Information: | Nature Portfolio, 2021. |
| Publication Year: | 2021 |
| Collection: | LCC:Medicine LCC:Science |
| Subject Terms: | Medicine, Science |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2045-2322 |
| Relation: | https://doaj.org/toc/2045-2322 |
| DOI: | 10.1038/s41598-021-84647-2 |
| Access URL: | https://doaj.org/article/cb7c285f227c42abb04cd250bb2d752a |
| Accession Number: | edsdoj.b7c285f227c42abb04cd250bb2d752a |
| Database: | Directory of Open Access Journals |
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| ISSN: | 20452322 |
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| DOI: | 10.1038/s41598-021-84647-2 |
| Published in: | Scientific Reports |
| Language: | English |