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

Academic Article

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

    Published In

  • Scientific Reports  Journal
  • Keywords

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

    Pubmed Id

  • 24522462
  • Author List

  • Shaw TI; Dong L; Tian L; Qian C; Liu Y; Ju B; High A; Kavdia K; Pagala VR; Shaner B
  • Start Page

  • 5154
  • Volume

  • 11
  • Issue

  • 1