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

• Published in: Scientific reports Vol. 11; no. 1; pp. 5154 - 12
• Main Authors: Shaw, Timothy I., Dong, Li, Tian, Liqing, Qian, Chenxi, Liu, Yu, Ju, Bensheng, High, Anthony, Kavdia, Kanisha, Pagala, Vishwajeeth R., Shaner, Bridget, Pei, Deqing, Easton, John, Janke, Laura J., Porter, Shaina N., Ma, Xiaotu, Cheng, Cheng, Pruett-Miller, Shondra M., Choi, John, Yu, Jiyang, Peng, Junmin, Gu, Wei, Look, A. Thomas, Downing, James R., Zhang, Jinghui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.03.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114; 631/114/2114; 631/67/1990/283/2125; Acute lymphoblastic leukemia; Cell Line, Tumor; Cell Lineage - genetics; Cell Proliferation - genetics; CRISPR; CRISPR-Cas Systems - genetics; Dosage; Drug development; Gene Expression Regulation, Leukemic - genetics; Gene regulation; Haploinsufficiency; Haploinsufficiency - genetics; Humanities and Social Sciences; Humans; Leukemia; Lymphatic leukemia; Lymphocytes T; Mass spectrometry; Mass spectroscopy; multidisciplinary; Oncogenes - genetics; Pediatrics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proteins; Science; Science (multidisciplinary); Synergistic effect; T-Cell Acute Lymphocytic Leukemia Protein 1 - genetics; Transcription; Transcriptional Activation - genetics; Tumor suppressor genes; Ubiquitin-Specific Peptidase 7 - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84647-2

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.