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

Affiliation

Shaw TI(#)(1), Dong L(#)(1), Tian L(1), Qian C(1), Liu Y(1), Ju B(1), High A(2), Kavdia K(2), Pagala VR(2), Shaner B(1), Pei D(3), Easton J(1), Janke LJ(4), Porter SN(5), Ma X(1), Cheng C(3), Pruett-Miller SM(5), Choi J(4), Yu J(1), Peng J(2)(6), Gu W(7), Look AT(8), Downing JR(4), Zhang J(9).
Author information:
(1)Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS321, Memphis, TN, 38105, USA.
(2)Center for Proteomics and Metabolomics, St Jude Children's Research Hospital, Memphis, USA.
(3)Department of Biostatistics, St Jude Children's Research Hospital, Memphis, USA.
(4)Department of Pathology, St Jude Children's Research Hospital, Memphis, USA.
(5)Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, USA.
(6)Departments of Structural Biology and Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, USA.
(7)Department of Pathology and Cell Biology and Institute for Cancer Genetics, Columbia University, New York, USA.
(8)Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA.
(9)Department of Computational Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS321, Memphis, TN, 38105, USA. [Email]
(#)Contributed equally

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.