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

Sci Rep. 2021 Mar 4;11(1):5154. doi: 10.1038/s41598-021-84647-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • T-Cell Acute Lymphocytic Leukemia Protein 1 / genetics*
  • Transcriptional Activation / genetics
  • Ubiquitin-Specific Peptidase 7 / genetics*

Substances

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