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 > 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.

• 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
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 5154 (03 04 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33664368 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• T-Cell Acute Lymphocytic Leukemia Protein 1
• TAL1 protein, human
• USP7 protein, human
• Ubiquitin-Specific Peptidase 7

Topics

• CRISPR-Cas Systems (genetics)
• Cell Line, Tumor
• Cell Lineage (genetics)
• Cell Proliferation (genetics)
• Gene Expression Regulation, Leukemic (genetics)
• Haploinsufficiency (genetics)
• Humans
• Oncogenes (genetics)
• Pediatrics
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, pathology)
• T-Cell Acute Lymphocytic Leukemia Protein 1 (genetics)
• Transcriptional Activation (genetics)
• Ubiquitin-Specific Peptidase 7 (genetics)