Scientific Reports (Mar 2021)

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

  • 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

DOI
https://doi.org/10.1038/s41598-021-84647-2
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 12

Abstract

Read online

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.